Is EIF2B2 p.Val225Ile (c.673G>A) pathogenic?

EIF2B2 p.Val225Ile (c.673G>A) is classified Uncertain significance in EIF2B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely benign (0.1156); Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with EIF2B2 p.Val225Ile (c.673G>A)?

EIF2B2 p.Val225Ile (c.673G>A) is associated with Inborn genetic diseases (ClinVar).

How common is EIF2B2 p.Val225Ile (c.673G>A) in the general population?

EIF2B2 p.Val225Ile (c.673G>A) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about EIF2B2 p.Val225Ile (c.673G>A)?

AlphaMissense predicts likely benign (score 0.1156) — an in-silico prediction, not a clinical call.

EIF2B2 p.Val225Ile

c.673G>A · VCV4247696

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1156 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1156	likely benign
REVEL	0.446	indeterminate
SaProt	LLR -7.77	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 6,194 bp · p 4.2e-05 · regional, not allelic
Overall
CADD	23.2	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 0.0107% African / African-American · 8/74,876 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00124% 20/1,613,018 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,360
East Asian	0.00446%	22,418
Remaining individualsnot grpmax-eligible	0.0016%	62,424
Finnishnot grpmax-eligible	0.00156%	63,956
South Asian	0.0011%	91,050
European (non-Finnish)	0.000594%	168,476

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: EIF2B2
Protein: p.Val225Ile
Coding: c.673G>A
MANE Select: NM_014239
Type: single nucleotide variant
Location: chr14:75005941 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.82 · 38 PDB
Residue 225: an α-helix

Full EIF2B2 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

EIF2B2 p.Ala195Ser Uncertain significance ★★ ⚠ same condition
EIF2B2 p.Ala6Pro Uncertain significance ★★ ⚠ same condition
EIF2B2 p.Arg43Cys Uncertain significance ★★ ⚠ same condition
EIF2B2 p.His286Arg Uncertain significance ★★ ⚠ same condition
EIF2B2 p.Ile151Thr Uncertain significance ★★ ⚠ same condition
EIF2B2 p.Ile190Met Uncertain significance ★★ ⚠ same condition
EIF2B2 p.Ile222Val Uncertain significance ★★ ⚠ same condition
EIF2B2 p.Lys179Arg 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/eif2b2-p-val225ile (accessed [today's date]).

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