Is EIF2B4 p.Pro145Ser (c.433C>T) pathogenic?

EIF2B4 p.Pro145Ser (c.433C>T) is classified Likely benign in EIF2B4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-22). AlphaMissense: likely benign (0.0901); Ultra-rare (popmax 0.0583%, amr).

How common is EIF2B4 p.Pro145Ser (c.433C>T) in the general population?

EIF2B4 p.Pro145Ser (c.433C>T) is ultra-rare (popmax 0.0583%, amr) (gnomAD).

What do computational predictors say about EIF2B4 p.Pro145Ser (c.433C>T)?

AlphaMissense predicts likely benign (score 0.0901) — an in-silico prediction, not a clinical call.

EIF2B4 p.Pro145Ser

c.433C>T · rs750850634 · VCV1461659

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0901 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0583%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0901	likely benign
REVEL	0.277	benign-leaning
SaProt	LLR -6.48	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP -2.3, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 5,450 bp · p 0.8 · regional, not allelic
Overall
CADD	17.12	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 0.0583% Admixed American · 35/59,988 alleles

Filtering AF 0.0431% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0378%

Overall 0.00328% 53/1,614,010 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0583%	1,714
South Asian	0.0176%	5,693
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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: EIF2B4
Protein: p.Pro145Ser
Coding: c.433C>T
MANE Select: NM_001034116
dbSNP: rs750850634
Type: single nucleotide variant
Location: chr2:27368719 (GRCh38)
Gene constraint: LOEUF 0.687 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.37 · 38 PDB
Residue 145: the 'disordered' region

Full EIF2B4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EIF2B4 c.32-1G>T Likely pathogenic ★★ same type
EIF2B4 p.Arg357Gln Likely pathogenic ★★ ⚠ same type
EIF2B4 p.Pro243Leu Pathogenic/Likely pathogenic ★★ ⚠ same type
EIF2B4 p.Thr502Met Likely pathogenic ★★ same type
EIF2B4 p.Tyr489His Pathogenic/Likely pathogenic ★★ same type
EIF2B4 p.Ala228Thr Uncertain significance ★★ ⚠ same type
EIF2B4 p.Ala349Thr Uncertain significance ★★ ⚠ same type
EIF2B4 p.Ala66Thr Uncertain significance ★★ ⚠ 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/eif2b4-p-pro145ser (accessed [today's date]).

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