Is EIF4G3 p.Pro735Ser (c.2203C>T) pathogenic?

EIF4G3 p.Pro735Ser (c.2203C>T) is classified Uncertain significance in EIF4G3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-25). AlphaMissense: likely pathogenic (0.9883); Very rare (popmax 0.00134%, afr).

How common is EIF4G3 p.Pro735Ser (c.2203C>T) in the general population?

EIF4G3 p.Pro735Ser (c.2203C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about EIF4G3 p.Pro735Ser (c.2203C>T)?

AlphaMissense predicts likely pathogenic (score 0.9883) — an in-silico prediction, not a clinical call.

EIF4G3 p.Pro735Ser

c.2203C>T · VCV3507698

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9883 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9883	likely pathogenic · top 9% in EIF4G3
REVEL	0.398	indeterminate
SaProt	LLR -6.61	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 16 kb · p 0.00011 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P679S vs ClinVar P735S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,746 alleles

Overall 0.000657% 1/152,098 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.Pro735Ser
Coding: c.2203C>T
MANE Select: NM_001391906
Type: single nucleotide variant
Location: chr1:20893567 (GRCh38)
Gene constraint: LOEUF 0.213 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.22 · 1 PDB
Residue 735: the 'eif3/eif4a-binding' region; 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-pro735ser (accessed [today's date]).

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