Is EIF2B3 p.Arg91Cys (c.271C>T) pathogenic?

EIF2B3 p.Arg91Cys (c.271C>T) is classified Uncertain significance in EIF2B3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-20). AlphaMissense: ambiguous (0.5049); Ultra-rare (popmax 0.0134%, afr).

How common is EIF2B3 p.Arg91Cys (c.271C>T) in the general population?

EIF2B3 p.Arg91Cys (c.271C>T) is ultra-rare (popmax 0.0134%, afr) (gnomAD).

What do computational predictors say about EIF2B3 p.Arg91Cys (c.271C>T)?

AlphaMissense predicts ambiguous (score 0.5049) — an in-silico prediction, not a clinical call.

EIF2B3 p.Arg91Cys

c.271C>T · rs772111952 · VCV2141399

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5049 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5049	ambiguous
REVEL	0.829	moderately pathogenic-leaning
SaProt	LLR -13.80	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 2,836 bp · p 0.054 · regional, not allelic
Overall
CADD	28.5	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 0.0134% African / African-American · 10/74,888 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.00254% 41/1,613,856 alleles · ultra-rare exomes 33/1,461,764 · genomes 8/152,092 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0134%	7,489
Admixed American	0.0117%	8,567
Remaining individualsnot grpmax-eligible	0.0032%	31,240
South Asian	0.0022%	45,542
European (non-Finnish)	0.00169%	59,001

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: EIF2B3
Protein: p.Arg91Cys
Coding: c.271C>T
MANE Select: NM_020365
dbSNP: rs772111952
Type: single nucleotide variant
Location: chr1:44978338 (GRCh38)
Gene constraint: LOEUF 0.522 · pLI 0.93 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 72.51 · 37 PDB
Residue 91: an α-helix

Full EIF2B3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EIF2B3 p.Arg91His Conflicting classifications of pathogenicity ★ ⚠ same residue
EIF2B3 p.Ala87Val Pathogenic/Likely pathogenic ★★ same type
EIF2B3 p.Arg225Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
EIF2B3 p.Arg225Trp Likely pathogenic ★★ same type
EIF2B3 p.Ile346Thr Pathogenic/Likely pathogenic ★★ ⚠ same type
EIF2B3 p.Val30Ala Pathogenic/Likely pathogenic ★★ same type
EIF2B3 c.784+4A>C Uncertain significance ★★ same type
EIF2B3 c.*55C>T 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/eif2b3-p-arg91cys (accessed [today's date]).

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