Is EIF2B2 p.Pro196Ser (c.586C>T) pathogenic?

EIF2B2 p.Pro196Ser (c.586C>T) is classified Likely pathogenic in EIF2B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-12). AlphaMissense: likely pathogenic (0.9256); Very rare (popmax 0.00212%, nfe).

How common is EIF2B2 p.Pro196Ser (c.586C>T) in the general population?

EIF2B2 p.Pro196Ser (c.586C>T) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about EIF2B2 p.Pro196Ser (c.586C>T)?

AlphaMissense predicts likely pathogenic (score 0.9256) — an in-silico prediction, not a clinical call.

EIF2B2 p.Pro196Ser

c.586C>T · rs113994011 · VCV3252687

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9256 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9256	likely pathogenic ✓ concordant with ClinVar
REVEL	0.967	strongly pathogenic-leaning
SaProt	LLR -13.46	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 6,194 bp · p 4.2e-05 · 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 0.00212% European (non-Finnish) · 25/1,178,732 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00161% 26/1,610,916 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00212%	47,149
Remaining individualsnot grpmax-eligible	0.0016%	62,340

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: EIF2B2
Protein: p.Pro196Ser
Coding: c.586C>T
MANE Select: NM_014239
dbSNP: rs113994011
Type: single nucleotide variant
Location: chr14:75004889 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.82 · 38 PDB
Residue 196: a β-strand; a UniProt-annotated variant site (in vwm2)

Full EIF2B2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EIF2B2 c.285-1G>A Likely pathogenic ★★ same type
EIF2B2 c.832-2A>G Likely pathogenic ★★ same type
EIF2B2 p.Arg172Ter Pathogenic/Likely pathogenic ★★ same type
EIF2B2 p.Arg183Ter Pathogenic/Likely pathogenic ★★ same type
EIF2B2 p.Glu213Gly Pathogenic ★★ same type
EIF2B2 p.Glu304Ter Pathogenic/Likely pathogenic ★★ same type
EIF2B2 p.Gly200Val Pathogenic/Likely pathogenic ★★ same type
EIF2B2 p.Lys273Arg Pathogenic/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/eif2b2-p-pro196ser (accessed [today's date]).

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