Is EIF4A2 p.Phe376= (c.1128T>C) pathogenic?

EIF4A2 p.Phe376= (c.1128T>C) is classified Likely benign in EIF4A2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-03-08). Very rare (popmax 0.00223%, eas); Associated with EIF4A2-related disorder.

What condition is associated with EIF4A2 p.Phe376= (c.1128T>C)?

EIF4A2 p.Phe376= (c.1128T>C) is associated with EIF4A2-related disorder (ClinVar).

How common is EIF4A2 p.Phe376= (c.1128T>C) in the general population?

EIF4A2 p.Phe376= (c.1128T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

EIF4A2 p.Phe376=

c.1128T>C · VCV3353118

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

EIF4A2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Overall
CADD	10.15	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,890 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00155% 25/1,613,734 alleles · very rare exomes 23/1,461,530 · genomes 2/152,204 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,890
European (non-Finnish)	0.00195%	51,297
Remaining individualsnot grpmax-eligible	0.0016%	62,462

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: EIF4A2
Protein: p.Phe376=
Coding: c.1128T>C
MANE Select: NM_001967
Type: single nucleotide variant
Location: chr3:186789173 (GRCh38)
Gene constraint: LOEUF 0.298 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.94 · 1 PDB
Residue 376: the helicase c-terminal domain

Full EIF4A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

EIF4A2-related disorder

Similar variants

EIF4A2 p.Arg335His Uncertain significance ★ ⚠ same condition
EIF4A2 c.518-7C>T Benign same condition
EIF4A2 c.771+5C>T Likely benign same condition
EIF4A2 c.772-3C>T Benign same condition
EIF4A2 c.-8T>C Likely benign same condition
EIF4A2 p.Lys248= Benign same condition
EIF4A2 p.Tyr8= Likely benign same condition
EIF4A2 p.Val141= Likely benign same condition

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/eif4a2-p-phe376 (accessed [today's date]).

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