Is EIF4E1B p.Val94Ala (c.281T>C) pathogenic?

EIF4E1B p.Val94Ala (c.281T>C) is classified Uncertain significance in EIF4E1B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.2182); Ultra-rare (popmax 0.0785%, amr).

How common is EIF4E1B p.Val94Ala (c.281T>C) in the general population?

EIF4E1B p.Val94Ala (c.281T>C) is ultra-rare (popmax 0.0785%, amr) (gnomAD).

What do computational predictors say about EIF4E1B p.Val94Ala (c.281T>C)?

AlphaMissense predicts likely benign (score 0.2182) — an in-silico prediction, not a clinical call.

EIF4E1B p.Val94Ala

c.281T>C · VCV4247863

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2182 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0785%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2182	likely benign
REVEL	0.362	indeterminate
SaProt	LLR -9.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.1	GERP 0.96, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 3,189 bp · p 0.22 · regional, not allelic
Overall
CADD	23.7	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0785% Admixed American · 47/59,848 alleles

Filtering AF 0.0606% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0543%

Overall 0.00614% 99/1,612,884 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0785%	1,273
Remaining individualsnot grpmax-eligible	0.00961%	10,404
European (non-Finnish)	0.00382%	26,212
African / African-American	0.00133%	74,912

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: EIF4E1B
Protein: p.Val94Ala
Coding: c.281T>C
MANE Select: NM_001099408
Type: single nucleotide variant
Location: chr5:176643719 (GRCh38)
Gene constraint: LOEUF 1.085 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.43

Full EIF4E1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EIF4E1B p.Ala195Val Uncertain significance ★ ⚠ same type
EIF4E1B p.Ala226Val Uncertain significance ★ ⚠ same type
EIF4E1B p.Arg134Trp Uncertain significance ★ ⚠ same type
EIF4E1B p.Arg147Ser Uncertain significance ★ ⚠ same type
EIF4E1B p.Arg153Trp Uncertain significance ★ ⚠ same type
EIF4E1B p.Arg172Gly Uncertain significance ★ ⚠ same type
EIF4E1B p.Arg193Gly Uncertain significance ★ ⚠ same type
EIF4E1B p.Arg193Ser 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/eif4e1b-p-val94ala (accessed [today's date]).

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