Is EIF3B p.Pro40Ser (c.118C>T) pathogenic?

EIF3B p.Pro40Ser (c.118C>T) is classified Uncertain significance in EIF3B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-20). AlphaMissense: likely benign (0.0754); Very rare (popmax 0.0035%, nfe).

How common is EIF3B p.Pro40Ser (c.118C>T) in the general population?

EIF3B p.Pro40Ser (c.118C>T) is very rare (popmax 0.0035%, nfe) (gnomAD).

What do computational predictors say about EIF3B p.Pro40Ser (c.118C>T)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

EIF3B p.Pro40Ser

c.118C>T · VCV3507562

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0035%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -6.51	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 -0.86	GERP -1.4
Regional constraint	o/e 1.21	unconstrained · MANE · 8,186 bp · p 3.2e-05 · regional, not allelic
Overall
CADD	13.7	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 0.0035% European (non-Finnish) · 34/970,682 alleles

Filtering AF 0.00252% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00222%

Overall 0.00283% 34/1,203,484 alleles · very 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: EIF3B
Protein: p.Pro40Ser
Coding: c.118C>T
MANE Select: NM_001037283
Type: single nucleotide variant
Location: chr7:2355039 (GRCh38)
Gene constraint: LOEUF 0.107 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.64 · 21 PDB
Residue 40: the 'disordered' region

Full EIF3B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EIF3B p.Pro40Thr Uncertain significance ★ ⚠ same residue
EIF3B p.Asn145= Benign ★★ same type
EIF3B p.Pro24= Likely benign ★★ same type
EIF3B p.Ser64Pro Benign ★★ same type
EIF3B c.1357-16C>T Uncertain significance ★ same type
EIF3B p.Ala123Thr Uncertain significance ★ ⚠ same type
EIF3B p.Ala135Pro Uncertain significance ★ ⚠ same type
EIF3B p.Ala136Val 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/eif3b-p-pro40ser (accessed [today's date]).

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