Is EIF4A2 p.Pro153Ser (c.457C>T) pathogenic?

EIF4A2 p.Pro153Ser (c.457C>T) is classified Uncertain significance in EIF4A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: likely pathogenic (0.7938); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EIF4A2 p.Pro153Ser (c.457C>T)?

EIF4A2 p.Pro153Ser (c.457C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EIF4A2 p.Pro153Ser (c.457C>T) in the general population?

EIF4A2 p.Pro153Ser (c.457C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about EIF4A2 p.Pro153Ser (c.457C>T)?

AlphaMissense predicts likely pathogenic (score 0.7938) — an in-silico prediction, not a clinical call.

EIF4A2 p.Pro153Ser

c.457C>T · rs1721678979 · VCV2245064

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7938 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7938	likely pathogenic
REVEL	0.138	moderately benign-leaning
SaProt	LLR -14.62	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.32	constrained · MANE · 3,070 bp · p 3.3e-38 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,350 alleles

Overall 6.84e-05% 1/1,461,094 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: EIF4A2
Protein: p.Pro153Ser
Coding: c.457C>T
MANE Select: NM_001967
dbSNP: rs1721678979
Type: single nucleotide variant
Location: chr3:186785991 (GRCh38)
Gene constraint: LOEUF 0.298 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.94 · 1 PDB
Residue 153: the helicase atp-binding domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EIF4A2 p.Gly362Ser Pathogenic ★★ same condition
EIF4A2 p.Ile278Thr Uncertain significance ★★ ⚠ same condition
EIF4A2 p.Asp338Tyr Likely pathogenic ★ same condition
EIF4A2 p.Ala302Ser Uncertain significance ★ ⚠ same condition
EIF4A2 p.Ala6Thr Uncertain significance ★ ⚠ same condition
EIF4A2 p.Asn27Ser Uncertain significance ★ ⚠ same condition
EIF4A2 p.Gln249Glu Uncertain significance ★ ⚠ same condition
EIF4A2 p.Glu380Asp Uncertain significance ★ 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-pro153ser (accessed [today's date]).

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