Is GAPDH p.Pro252Arg (c.755C>G) pathogenic?

GAPDH p.Pro252Arg (c.755C>G) is classified Uncertain significance in GAPDH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: ambiguous (0.3415); Very rare (popmax 0.00134%, afr).

How common is GAPDH p.Pro252Arg (c.755C>G) in the general population?

GAPDH p.Pro252Arg (c.755C>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about GAPDH p.Pro252Arg (c.755C>G)?

AlphaMissense predicts ambiguous (score 0.3415) — an in-silico prediction, not a clinical call.

GAPDH p.Pro252Arg

c.755C>G · rs1946517126 · VCV3098310

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3415 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3415	ambiguous
REVEL	0.235	benign-leaning
SaProt	LLR -12.59	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 3,334 bp · p 9.1e-12 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,858 alleles

Overall 6.2e-05% 1/1,611,874 alleles · very rare exomes 0/1,459,656 · genomes 1/152,218 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GAPDH
Protein: p.Pro252Arg
Coding: c.755C>G
MANE Select: NM_002046
dbSNP: rs1946517126
Type: single nucleotide variant
Location: chr12:6537813 (GRCh38)
Gene constraint: LOEUF 0.679 · pLI 0.19 (gnomAD)
Structure: AlphaFold pLDDT 98.17 · 23 PDB

Full GAPDH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GAPDH c.-8C>G Benign ★★ same type
NCAPD2 c.4120+2T>C Pathogenic ★ same type
GAPDH p.Ala265Thr Uncertain significance ★ same type
GAPDH p.Arg118Ser Uncertain significance ★ ⚠ same type
GAPDH p.Arg323Lys Uncertain significance ★ ⚠ same type
GAPDH p.Asn304Ser Uncertain significance ★ ⚠ same type
GAPDH p.Asp198Gly Uncertain significance ★ ⚠ same type
GAPDH p.His165Arg Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/gapdh-p-pro252arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown