H6PD

Chr 1AR

hexose-6-phosphate dehydrogenase/glucose 1-dehydrogenase

Also known as: CORTRD1, G6PDH, GDH, H6PDH

NCBI Gene: 9563 ENSG00000049239 UniProt: O95479 OMIM: 138090

The H6PD protein is a bifunctional enzyme in the endoplasmic reticulum that catalyzes the first two steps of the pentose phosphate pathway and provides NADPH reducing equivalents needed by ER reductases, including corticosteroid 11-beta-dehydrogenase. Mutations cause cortisone reductase deficiency 1, inherited in an autosomal recessive pattern. This gene shows low constraint against loss-of-function variants (pLI near zero), consistent with recessive inheritance where single allele loss is typically tolerated.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

There are 2 forms of glucose-6-phosphate dehydrogenase. G form is X-linked and H form, encoded by this gene, is autosomally linked. This H form shows activity with other hexose-6-phosphates, especially galactose-6-phosphate, whereas the G form is specific for glucose-6-phosphate. Both forms are present in most tissues, but H form is not found in red cells. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.941 OMIM phenotype

Clinical Summary— H6PD

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

8 unique Pathogenic / Likely Pathogenic· 180 VUS of 326 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.94LOEUF

pLI 0.000

Z-score 1.80

OE 0.63 (0.43–0.94)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-1.13Z-score

OE missense 1.15 (1.07–1.23)

549 obs / 479.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.63 (0.43–0.94)

0≤0.351.4

Missense OE?1.15 (1.07–1.23)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 17 / 27.1Missense obs/exp: 549 / 479.2Syn Z: -1.74

This gene — mechanism propensity

0.6743th %ile

GOF

0.6737th %ile

LOF

0.2776th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

326 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic2

VUS180

Likely Benign79

Benign40

Conflicting9

Pathogenic

Likely Pathogenic

180

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	1	0	1	6
Likely Pathogenic	2	0	0	0	2
VUS	2	176	2	0	180
Likely Benign	0	21	8	50	79
Benign	1	11	7	21	40
Conflicting	—				9
Total	9	209	17	72	316

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

40 pathogenic / likely-pathogenic (of 50) ClinVar copy-number / structural variants overlap H6PD — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →