Is EIF2B2 p.Ala195Ser (c.583G>T) pathogenic?

EIF2B2 p.Ala195Ser (c.583G>T) is classified Uncertain significance in EIF2B2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-29). AlphaMissense: likely benign (0.107); Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with EIF2B2 p.Ala195Ser (c.583G>T)?

EIF2B2 p.Ala195Ser (c.583G>T) is associated with Inborn genetic diseases (ClinVar).

How common is EIF2B2 p.Ala195Ser (c.583G>T) in the general population?

EIF2B2 p.Ala195Ser (c.583G>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about EIF2B2 p.Ala195Ser (c.583G>T)?

AlphaMissense predicts likely benign (score 0.107) — an in-silico prediction, not a clinical call.

EIF2B2 p.Ala195Ser

c.583G>T · VCV4618337

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.107 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.107	likely benign
REVEL	0.725	pathogenic-leaning
SaProt	LLR -7.61	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	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	25.3	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 0.0107% African / African-American · 8/74,630 alleles

Filtering AF 0.0053% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00382%

Overall 0.000496% 8/1,611,320 alleles · ultra-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: EIF2B2
Protein: p.Ala195Ser
Coding: c.583G>T
MANE Select: NM_014239
Type: single nucleotide variant
Location: chr14:75004886 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.82 · 38 PDB
Residue 195: a β-strand

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.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
EIF2B2 p.Pro276Ser 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-ala195ser (accessed [today's date]).

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