Is EIF4E2 p.Arg103His (c.308G>A) pathogenic?

EIF4E2 p.Arg103His (c.308G>A) is classified Uncertain significance in EIF4E2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-07). AlphaMissense: likely pathogenic (0.9518); Ultra-rare (popmax 0.0223%, eas).

How common is EIF4E2 p.Arg103His (c.308G>A) in the general population?

EIF4E2 p.Arg103His (c.308G>A) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about EIF4E2 p.Arg103His (c.308G>A)?

AlphaMissense predicts likely pathogenic (score 0.9518) — an in-silico prediction, not a clinical call.

EIF4E2 p.Arg103His

c.308G>A · rs921725664 · VCV2325104

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9518 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9518	likely pathogenic
REVEL	0.325	indeterminate
SaProt	LLR -10.65	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 11 kb · p 1.1e-10 · regional, not allelic
Overall
CADD	29.0	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 0.0223% East Asian · 10/44,754 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00919%

Overall 0.00125% 20/1,599,516 alleles · ultra-rare exomes 17/1,447,368 · genomes 3/152,148 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,475
African / African-American	0.00401%	24,932
Remaining individualsnot grpmax-eligible	0.00161%	61,942
South Asian	0.00113%	88,266
European (non-Finnish)	0.000427%	234,409

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.Arg103His
Coding: c.308G>A
MANE Select: NM_004846
dbSNP: rs921725664
Type: single nucleotide variant
Location: chr2:232564284 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI 0.08 (gnomAD)
Structure: AlphaFold pLDDT 80.42 · 7 PDB

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.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
EIF4E2 p.Arg241Trp 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-arg103his (accessed [today's date]).

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