Is EIF2B2 p.Val316Asp (c.947T>A) pathogenic?

EIF2B2 p.Val316Asp (c.947T>A) is classified Pathogenic/Likely pathogenic in EIF2B2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-02-23). AlphaMissense: likely pathogenic (0.9991); Very rare (popmax 0.00223%, eas); Associated with leukoencephalopathy with vanishing white matter 2.

What condition is associated with EIF2B2 p.Val316Asp (c.947T>A)?

EIF2B2 p.Val316Asp (c.947T>A) is associated with leukoencephalopathy with vanishing white matter 2, leukoencephalopathy with vanishing white matter (ClinVar).

How common is EIF2B2 p.Val316Asp (c.947T>A) in the general population?

EIF2B2 p.Val316Asp (c.947T>A) is very rare (popmax 0.00223%, eas) (gnomAD).

How is CACH syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about EIF2B2 p.Val316Asp (c.947T>A)?

AlphaMissense predicts likely pathogenic (score 0.9991) — an in-silico prediction, not a clinical call.

EIF2B2 p.Val316Asp

c.947T>A · rs104894426 · VCV4337

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukoencephalopathy with vanishing white matter 2

Computational evidence

Protein change
AlphaMissense	0.9991	likely pathogenic ✓ concordant with ClinVar · top 1% in EIF2B2
REVEL	0.988	strongly pathogenic-leaning
SaProt	LLR -14.33	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 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 6,194 bp · p 4.2e-05 · regional, not allelic
Overall
CADD	32.0	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 0.00223% East Asian · 1/44,896 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000682% 11/1,614,024 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,896
African / African-American	0.00133%	74,910
European (non-Finnish)	0.000763%	131,112

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.Val316Asp
Coding: c.947T>A
MANE Select: NM_014239
dbSNP: rs104894426
Type: single nucleotide variant
Location: chr14:75009079 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.82 · 38 PDB
Residue 316: a β-strand; a UniProt-annotated variant site (in vwm2)

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

Disease context

leukoencephalopathy with vanishing white matter 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: leukoencephalopathy with vanishing white matter

For CACH syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

EIF2B2 p.Val316Phe Likely pathogenic ★ same residue
EIF2B2 p.Val316Ile Uncertain significance ★ ⚠ same residue
EIF2B2 p.Val316= Likely benign ★ same residue
EIF2B2 c.285-1G>A Likely pathogenic ★★ same condition
EIF2B2 c.832-2A>G Likely pathogenic ★★ same condition
EIF2B2 p.Arg183Ter Pathogenic/Likely pathogenic ★★ same condition
EIF2B2 p.Glu213Gly Pathogenic ★★ ⚠ same condition
EIF2B2 p.Glu304Ter Pathogenic/Likely pathogenic ★★ 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-val316asp (accessed [today's date]).

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