Is EIF2B5 p.Pro545Ser (c.1633C>T) pathogenic?

EIF2B5 p.Pro545Ser (c.1633C>T) is classified Uncertain significance in EIF2B5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-13). AlphaMissense: likely benign (0.2541); Absent from gnomAD v4.1.

How common is EIF2B5 p.Pro545Ser (c.1633C>T) in the general population?

EIF2B5 p.Pro545Ser (c.1633C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EIF2B5 p.Pro545Ser (c.1633C>T)?

AlphaMissense predicts likely benign (score 0.2541) — an in-silico prediction, not a clinical call.

EIF2B5 p.Pro545Ser

c.1633C>T · rs2473670356 · VCV1984520

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2541 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2541	likely benign
REVEL	0.643	indeterminate
SaProt	LLR -6.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.81, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,264 bp · p 4.1e-06 · regional, not allelic
Overall
CADD	25.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EIF2B5
Protein: p.Pro545Ser
Coding: c.1633C>T
MANE Select: NM_003907
dbSNP: rs2473670356
Type: single nucleotide variant
Location: chr3:184142865 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 37 PDB
Residue 545: the w2 domain; the 'disordered' region

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

Similar variants

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
EIF2B5 p.Arg195His 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-pro545ser (accessed [today's date]).

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