Is EIF2S3 p.Ala2= (c.6G>A) pathogenic?

EIF2S3 p.Ala2= (c.6G>A) is classified Likely benign in EIF2S3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-01). Very rare (popmax 0.000782%, nfe).

How common is EIF2S3 p.Ala2= (c.6G>A) in the general population?

EIF2S3 p.Ala2= (c.6G>A) is very rare (popmax 0.000782%, nfe) (gnomAD).

EIF2S3 p.Ala2=

c.6G>A · VCV3905263

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000782%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.133	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.6	GERP -0.87, phastCons 0.002
Overall
CADD	6.953	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000782% European (non-Finnish) · 7/895,017 alleles

Filtering AF 0.000325% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000209%

Overall 0.000662% 8/1,208,922 alleles · very rare exomes 7/1,097,143 · genomes 1/111,779 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00219%	45,742
European (non-Finnish)grpmax	0.000782%	127,860

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: EIF2S3
Protein: p.Ala2=
Coding: c.6G>A
MANE Select: NM_001415
Type: single nucleotide variant
Location: chrX:24054974 (GRCh38)
Structure: AlphaFold pLDDT 85.34 · 29 PDB
Residue 2: a modified residue (n-acetylalanine; partial)

Full EIF2S3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EIF2S3 p.Ala2Gly Uncertain significance ★ ⚠ same residue
EIF2S3 p.Ala2Val Uncertain significance ★ ⚠ same residue
EIF2S3 p.Arg255Gln Uncertain significance ★★ ⚠ same type
EIF2S3 p.Ser104Ala Uncertain significance ★★ ⚠ same type
EIF2S3 p.Val245Leu Uncertain significance ★★ ⚠ same type
EIF2S3 c.133+8T>C Benign/Likely benign ★★ same type
EIF2S3 c.134-4A>G Likely benign ★★ same type
EIF2S3 p.Ala422= Benign ★★ 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/eif2s3-p-ala2 (accessed [today's date]).

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