Is EIF4G3 p.Arg332Pro (c.995G>C) pathogenic?

EIF4G3 p.Arg332Pro (c.995G>C) is classified Uncertain significance in EIF4G3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely benign (0.0933); Very rare (popmax 0.00834%, amr).

How common is EIF4G3 p.Arg332Pro (c.995G>C) in the general population?

EIF4G3 p.Arg332Pro (c.995G>C) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about EIF4G3 p.Arg332Pro (c.995G>C)?

AlphaMissense predicts likely benign (score 0.0933) — an in-silico prediction, not a clinical call.

EIF4G3 p.Arg332Pro

c.995G>C · VCV4247947

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0933 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0933	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -2.81	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 0.29	phastCons 0.022
Regional constraint	o/e 1.02	unconstrained · MANE · 74 kb · p 0.6 · regional, not allelic
Overall
CADD	15.98	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 R276P vs ClinVar R332P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00834% Admixed American · 5/59,986 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00031% 5/1,613,886 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.Arg332Pro
Coding: c.995G>C
MANE Select: NM_001391906
Type: single nucleotide variant
Location: chr1:20942159 (GRCh38)
Gene constraint: LOEUF 0.213 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.22 · 1 PDB
Residue 332: the 'disordered' region

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-arg332pro (accessed [today's date]).

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