Is EIF2B5 p.Pro4Ser (c.10C>T) pathogenic?

EIF2B5 p.Pro4Ser (c.10C>T) is classified Uncertain significance in EIF2B5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-28). AlphaMissense: likely benign (0.0868); Very rare (popmax 0.00191%, amr).

How common is EIF2B5 p.Pro4Ser (c.10C>T) in the general population?

EIF2B5 p.Pro4Ser (c.10C>T) is very rare (popmax 0.00191%, amr) (gnomAD).

What do computational predictors say about EIF2B5 p.Pro4Ser (c.10C>T)?

AlphaMissense predicts likely benign (score 0.0868) — an in-silico prediction, not a clinical call.

EIF2B5 p.Pro4Ser

c.10C>T · rs767998775 · VCV2171898

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0868 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00191%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0868	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -6.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.41	GERP -3.3
Regional constraint	o/e 1.16	unconstrained · MANE · 1,237 bp · p 0.11 · regional, not allelic
Overall
CADD	0.44	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 0.00191% Admixed American · 1/52,424 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000253% 4/1,579,066 alleles · very rare exomes 3/1,426,738 · genomes 1/152,328 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00191%	52,424
African / African-American	0.00134%	74,848
European (non-Finnish)	0.000172%	581,994

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: EIF2B5
Protein: p.Pro4Ser
Coding: c.10C>T
MANE Select: NM_003907
dbSNP: rs767998775
Type: single nucleotide variant
Location: chr3:184135395 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 37 PDB
Residue 4: the 'disordered' region

Full EIF2B5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EIF2B5 p.Pro4= Likely benign ★ same residue
EIF2B5 p.Ala403Val Pathogenic/Likely pathogenic ★★ ⚠ same type
EIF2B5 p.Arg113Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
EIF2B5 p.Arg113His Pathogenic ★★ ⚠ same type
EIF2B5 p.Arg121Ter Pathogenic/Likely pathogenic ★★ same type
EIF2B5 p.Arg136Cys Pathogenic/Likely pathogenic ★★ same type
EIF2B5 p.Arg136His Pathogenic ★★ same type
EIF2B5 p.Arg195Cys Likely pathogenic ★★ 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/eif2b5-p-pro4ser (accessed [today's date]).

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