Is EIF4E2 p.Pro55Ser (c.163C>T) pathogenic?

EIF4E2 p.Pro55Ser (c.163C>T) is classified Uncertain significance in EIF4E2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-18). AlphaMissense: likely pathogenic (0.6863); Ultra-rare (popmax 0.0267%, amr).

How common is EIF4E2 p.Pro55Ser (c.163C>T) in the general population?

EIF4E2 p.Pro55Ser (c.163C>T) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about EIF4E2 p.Pro55Ser (c.163C>T)?

AlphaMissense predicts likely pathogenic (score 0.6863) — an in-silico prediction, not a clinical call.

EIF4E2 p.Pro55Ser

c.163C>T · rs769552669 · VCV3087994

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6863 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6863	likely pathogenic
REVEL	0.508	indeterminate
SaProt	LLR -12.48	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 7,246 bp · p 0.49 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% Admixed American · 16/59,996 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00112% 18/1,613,768 alleles · ultra-rare exomes 17/1,461,604 · genomes 1/152,164 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,750
South Asian	0.0011%	91,068
European (non-Finnish)	8.47e-05%	1,179,962

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: EIF4E2
Protein: p.Pro55Ser
Coding: c.163C>T
MANE Select: NM_004846
dbSNP: rs769552669
Type: single nucleotide variant
Location: chr2:232557911 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI 0.08 (gnomAD)
Structure: AlphaFold pLDDT 80.42 · 7 PDB
Residue 55: the 'eif4ebp1/2/3 binding' region; a β-strand

Full EIF4E2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EIF4E2 p.Ala7Thr Uncertain significance ★ ⚠ same type
EIF4E2 p.Arg103His Uncertain significance ★ ⚠ same type
EIF4E2 p.Arg146His Uncertain significance ★ ⚠ same type
EIF4E2 p.Arg174Cys Uncertain significance ★ ⚠ same type
EIF4E2 p.Arg197Gln Uncertain significance ★ ⚠ same type
EIF4E2 p.Arg197Trp Uncertain significance ★ ⚠ same type
EIF4E2 p.Arg231Gly Uncertain significance ★ ⚠ same type
EIF4E2 p.Arg241Gln 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/eif4e2-p-pro55ser (accessed [today's date]).

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