GAPDH

Chr 12

glyceraldehyde-3-phosphate dehydrogenase

Also known as: G3PD, GAPD, HEL-S-162eP

NCBI Gene: 2597 ENSG00000111640 UniProt: P04406 OMIM: 138400

The protein catalyzes the conversion of glyceraldehyde-3-phosphate to 3-phospho-D-glyceroyl phosphate in glycolysis and serves multiple additional cellular functions including cytoskeletal organization, translation regulation, and innate immune signaling. Mutations in this gene cause autosomal dominant spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type, and severe combined immunodeficiency with hypereosinophilia. The gene shows moderate constraint against loss-of-function variants, suggesting some tolerance for certain types of mutations.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the glyceraldehyde-3-phosphate dehydrogenase protein family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. The product of this gene catalyzes an important energy-yielding step in carbohydrate metabolism, the reversible oxidative phosphorylation of glyceraldehyde-3-phosphate in the presence of inorganic phosphate and nicotinamide adenine dinucleotide (NAD). The encoded protein has additionally been identified to have uracil DNA glycosylase activity in the nucleus. Also, this protein contains a peptide that has antimicrobial activity against E. coli, P. aeruginosa, and C. albicans. Studies of a similar protein in mouse have assigned a variety of additional functions including nitrosylation of nuclear proteins, the regulation of mRNA stability, and acting as a transferrin receptor on the cell surface of macrophage. Many pseudogenes similar to this locus are present in the human genome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

941

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.67

LOEUF

GOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.67LOEUF

pLI 0.114

Z-score 2.43

OE 0.29 (0.14–0.67)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.81Z-score

OE missense 0.64 (0.56–0.74)

130 obs / 202.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.14–0.67)

0≤0.351.4

Missense OE?0.64 (0.56–0.74)

0≤0.61.4

Synonymous OE?1.51

0≤1.21.6

LoF obs/exp: 4 / 13.7Missense obs/exp: 130 / 202.6Syn Z: -3.60

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 220

339 rare PASS variants

Rare truncating (LoF)

1 in 390

58 rare PASS variants

Rare synonymous (reference)

1 in 190

226 rare PASS variants

Rare missense and truncating variants are carried at similar rates in GAPDH; this gene does not show strong loss-of-function constraint by this measure. 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 300	1 in 520
South Asian	~43k	1 in 210	1 in 850
Remaining (unassigned)	~30k	1 in 170	1 in 440
European (Finnish)	~27k	1 in 340	1 in 2,700
Admixed American	~22k	1 in 160	1 in 1,100
African / African American	~21k	1 in 230	1 in 1,200
East Asian	~20k	1 in 260	1 in 470
Ashkenazi Jewish	~13k	1 in 870	none seen
Middle Eastern	~2,884	1 in 450	≈ 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 8 coding exons well covered in gnomAD exomes and genomes.? see exons ↓