CausalSentinel

Protein Dossier — H6PD (GDH/6PGL endoplasmic bifunctional protein)

MR feasibility tier: A — Published pQTL-MR estimates exist for this protein (retrieved below - not computed here).

1. Published MR estimates (retrieved, not computed)

Outcome	beta	se	p	method	nSNP	cis/trans	coloc
Height	0.0578	0.0123	2.53e-06	Wald ratio	1	trans	NA
Knee and hip osteoarthritis	0.245	0.0863	0.00457	Wald ratio	1	trans	NA
Hip osteoarthritis	0.278	0.111	0.0119	Wald ratio	1	trans	NA
Eye problems or disorders: Injury or trauma resulting in loss of vision	-0.153	0.0615	0.0127	Inverse variance weighted	2	trans	NA
Eye problems or disorders: Injury or trauma resulting in loss of vision	-0.153	0.0615	0.0127	Inverse variance weighted	2	cis	NA
Serum cystatin C (eGFRcys)	-0.0181	0.00759	0.0173	Wald ratio	1	trans	NA
Type 2 diabetes	0.211	0.0962	0.0286	Wald ratio	1	trans	NA
Age at menopause	-0.145	0.0723	0.0455	Wald ratio	1	trans	NA
Non-cancer illness code self-reported: pneumothorax	0.296	0.151	0.0501	Inverse variance weighted	2	trans	NA
Non-cancer illness code self-reported: pneumothorax	0.296	0.151	0.0501	Inverse variance weighted	2	cis	NA
Clear cell ovarian cancer	-0.158	0.081	0.0511	Wald ratio	1	cis	NA
Non-cancer illness code self-reported: migraine	0.0423	0.0223	0.0581	Inverse variance weighted	2	trans	NA
…and 147 more outcomes (see JSON)

2. pQTL instrument availability (Tier-B probe)

No prot-* pQTL GWAS dataset found for this protein (matched by UniProt accession and symbol).

3. GWAS Catalog results — traits with signal at this locus

119 association rows across 54 traits (114 genome-wide significant rows). Associations are loci, not causal claims; the mapped gene at a locus is not necessarily the effector gene.

Trait	best p	lead SNP	n assoc	study	MR status
GDH/6PGL endoplasmic bifunctional protein levels	5e-323	rs2310925	4	GCST90247714	no MR -> candidate analysis
Height	4e-170	rs9434723	12	GCST90245848	MR: beta=0.0578, p=2.53e-06 (trans)
Serum levels of protein H6PD	1e-166	rs2310925	3	GCST90089703	no MR -> candidate analysis
height (mean, inv-normal transformed)	1e-140	rs9442580	2	GCST90475362	no MR -> candidate analysis
Height (maximum, inv-normal transformed)	1e-137	rs9442580	2	GCST90475359	no MR -> candidate analysis
GDH/6PGL endoplasmic bifunctional protein levels (H6PD.7161.	1e-126	rs34603401	2	GCST90241245	no MR -> candidate analysis
height (minimum, inv-normal transformed)	1e-112	rs9442571	2	GCST90475365	no MR -> candidate analysis
Blood protein levels	9e-96	rs9435144	1	GCST006585	no MR -> candidate analysis
What is your height? (cm, inv-normal transformed)	7e-73	rs9442571	2	GCST90475368	no MR -> candidate analysis
Standing height (UKB data field 50)	2e-46	rs9442571	1	GCST90468178	no MR -> candidate analysis
Height (baseline)	8e-40	rs658997	4	GCST90565843	no MR -> candidate analysis
H6PD protein levels	3e-32	rs2268174	3	GCST90453034	no MR -> candidate analysis
…and 42 more traits (see JSON)

4. Phenome map — where this gene is a genetic locus, vs. where MR exists

Top diseases by Open Targets association (of 461 total). Associations are loci, not causal claims. The causal-status column is a four-state triage per pair: established (curated) = a curated clinical assertion exists (ClinGen/G2P/GEL/Orphanet/ClinVar — any validity level, MR adds little); exploratory rare-variant signal = ExWAS burden evidence without curation — a candidate NEW gene-disease relationship; common-variant locus = GWAS signal, classic pQTL-MR territory; multi-layer = burden+GWAS together, an allelic-series candidate (the strongest causal setup). Burden estimand is carrier-vs-noncarrier, not per-SD MR.

Disease	genetic assoc.	burden (ExWAS)	causal status	MR status
Hyperandrogenism due to cortisone reductase deficiency	0.856	—	established (curated)	no MR -> candidate analysis
Abnormality of the skeletal system	0.789	—	common-variant locus	no MR -> candidate analysis
obesity disorder	0.55	—	common-variant locus	no MR -> candidate analysis
stroke disorder	0.463	—	common-variant locus	no MR -> candidate analysis
alcohol drinking	0.463	—	common-variant locus	no MR -> candidate analysis
placental retention	0.457	—	common-variant locus	no MR -> candidate analysis
hereditary disease	0.319	—	established (curated)	no MR -> candidate analysis
venous thromboembolism	0.236	—	common-variant locus	no MR -> candidate analysis
ventral hernia	0.222	—	common-variant locus	no MR -> candidate analysis
Inguinal hernia	0.194	—	common-variant locus	no MR -> candidate analysis
carpal tunnel syndrome	0.13	—	common-variant locus	no MR -> candidate analysis

Of the 11 rows above, 11 have no MR estimate in this resource. Across all retrieved diseases for this gene: 0 exploratory rare-variant signal(s), 0 multi-layer (allelic-series candidate) pair(s). Final triage still belongs to a statistical geneticist.

5. Downstream annotation (druggability & safety preview)

Layer	Result
ChEMBL druggability	not available — no ChEMBL target (undrugged)
gnomAD constraint	pLI=2.3e-13, LOEUF=0.998 — LoF-tolerant
GWAS Catalog	99 unique SNPs / 218 rows
ClinVar	378 records; 6 pathogenic in sample of 30
PharmGKB/ClinPGx	no annotations

Caveats declared by the tools

• phenome — Top 30 of 461 associated diseases by overall score. genetic_association aggregates GWAS common-variant AND rare-variant evidence. These are ASSOCIATIONS (loci), not causal claims.
• chembl — No ChEMBL target for ‘H6PD’.
• clinvar — Pathogenic count is over the 30 record(s) retrieved, NOT over all 378 ClinVar records for this gene; it is a sample, not a rate.
• pharmgkb — No PharmGKB/ClinPGx clinical annotations (gene may not be a pharmacogene).
• gwas_traits — Top 20 of 54 traits by best p-value, aggregated from 119 association rows. These are GWAS ASSOCIATIONS (loci), not causal claims; mapped genes at a locus are not necessarily the effector gene.

Sources

• uniprot: https://www.uniprot.org/uniprotkb/O95479 — UniProt release 2026_02 (10-June-2026)
• mr_outcomes: https://epigraphdb.org/pqtl/ — EpiGraphDB pQTL MR (Zheng et al., Nat Genet 2020) — pre-computed two-sample MR; retrieved, not computed by this agent; EpiGraphDB build 1.0, pQTL dataset v3.0
• phenome: https://platform.opentargets.org/target/ENSG00000049239/associations — Open Targets data release 26.06
• gnomad: https://gnomad.broadinstitute.org/gene/H6PD — gnomAD constraint via GraphQL API (reference genome GRCh38)
• gwas: https://www.ebi.ac.uk/gwas/genes/H6PD — GWAS Catalog REST (live; release not exposed by this endpoint)
• clinvar: https://www.ncbi.nlm.nih.gov/clinvar/?term=H6PD%5Bgene%5D — ClinVar build Build260809-1055.1
• gwas_traits: https://www.ebi.ac.uk/gwas/genes/H6PD — GWAS Catalog search API (live; release not exposed)

Provenance

• Generated: 2026-08-14T02:57:24 · Tier: A
• Fully mechanical: every cell above is rendered from tool return values. No language model wrote any part of this dossier.
• MR estimates, where present, are retrieved from published work (EpiGraphDB pQTL, Zheng et al. Nat Genet 2020); nothing is computed here.
• Tool errors this run: none

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