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…

Primary Disease Associations & Inheritance

Cortisone reductase deficiency 1MIM #604931

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Cortisone reductase deficiency 1; no ClinGen or GenCC tier

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.94

LOEUF

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in H6PD?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 21

1,182 rare PASS variants

Rare truncating (LoF)

1 in 760

143 rare PASS variants

Rare synonymous (reference)

1 in 48

511 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for H6PD. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 29	1 in 750
South Asian	~43k	1 in 27	1 in 1,100
Remaining (unassigned)	~30k	1 in 21	1 in 440
European (Finnish)	~27k	1 in 77	1 in 560
Admixed American	~22k	1 in 28	1 in 1,000
African / African American	~21k	1 in 26	1 in 1,100
East Asian	~20k	1 in 30	1 in 830
Ashkenazi Jewish	~13k	1 in 120	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 26	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 4 coding exons well covered in gnomAD exomes and genomes.? see exons ↓