Is EIF2B2 p.Val248Met (c.742G>A) pathogenic?

EIF2B2 p.Val248Met (c.742G>A) is classified Uncertain significance in EIF2B2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-09). AlphaMissense: likely benign (0.1914); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EIF2B2 p.Val248Met (c.742G>A)?

EIF2B2 p.Val248Met (c.742G>A) is associated with Inborn genetic diseases (ClinVar).

How common is EIF2B2 p.Val248Met (c.742G>A) in the general population?

EIF2B2 p.Val248Met (c.742G>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about EIF2B2 p.Val248Met (c.742G>A)?

AlphaMissense predicts likely benign (score 0.1914) — an in-silico prediction, not a clinical call.

EIF2B2 p.Val248Met

c.742G>A · rs956852835 · VCV1909159

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1914 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1914	likely benign
REVEL	0.44	indeterminate
SaProt	LLR -8.39	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 12	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	25.4	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 0.000254% European (non-Finnish) · 3/1,180,034 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,024 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: EIF2B2
Protein: p.Val248Met
Coding: c.742G>A
MANE Select: NM_014239
dbSNP: rs956852835
Type: single nucleotide variant
Location: chr14:75006625 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.82 · 38 PDB
Residue 248: a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EIF2B2 p.Val248= Likely benign ★ same residue
EIF2B2 p.Ala195Ser Uncertain significance ★★ ⚠ same condition
EIF2B2 p.Ala6Pro Uncertain significance ★★ ⚠ same condition
EIF2B2 p.Arg43Cys Uncertain significance ★★ ⚠ same condition
EIF2B2 p.His286Arg Uncertain significance ★★ ⚠ same condition
EIF2B2 p.Ile151Thr Uncertain significance ★★ ⚠ same condition
EIF2B2 p.Ile190Met Uncertain significance ★★ ⚠ same condition
EIF2B2 p.Ile222Val Uncertain significance ★★ ⚠ same condition

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-val248met (accessed [today's date]).

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