Is EIF4G3 p.Pro751Ser (c.2251C>T) pathogenic?

EIF4G3 p.Pro751Ser (c.2251C>T) is classified Uncertain significance in EIF4G3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-13). AlphaMissense: likely benign (0.0622); Very rare (popmax 0.00134%, afr).

How common is EIF4G3 p.Pro751Ser (c.2251C>T) in the general population?

EIF4G3 p.Pro751Ser (c.2251C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about EIF4G3 p.Pro751Ser (c.2251C>T)?

AlphaMissense predicts likely benign (score 0.0622) — an in-silico prediction, not a clinical call.

EIF4G3 p.Pro751Ser

c.2251C>T · rs2547575746 · VCV2344664

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0622 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0622	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -6.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP -1.1, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 16 kb · p 0.00011 · regional, not allelic
Overall
CADD	19.49	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P695S vs ClinVar P751S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,756 alleles

Overall 6.91e-05% 1/1,446,672 alleles · very rare

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: EIF4G3
Protein: p.Pro751Ser
Coding: c.2251C>T
MANE Select: NM_001391906
dbSNP: rs2547575746
Type: single nucleotide variant
Location: chr1:20893519 (GRCh38)
Gene constraint: LOEUF 0.213 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.22 · 1 PDB
Residue 751: the 'eif3/eif4a-binding' region; an α-helix

Full EIF4G3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EIF4G3 p.Met1383Thr Benign/Likely benign ★★ same type
EIF4G3 c.2253+798T>C Uncertain significance ★ same type
EIF4G3 c.2253+860G>A Uncertain significance ★ same type
EIF4G3 c.2253+863A>T Uncertain significance ★ same type
EIF4G3 c.2253+869C>T Uncertain significance ★ same type
EIF4G3 c.2253+879T>C Uncertain significance ★ same type
EIF4G3 c.2253+885G>A Uncertain significance ★ same type
EIF4G3 c.2253+894T>C 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/eif4g3-p-pro751ser (accessed [today's date]).

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