Is EIF2B2 p.Ser171Phe (c.512C>T) pathogenic?

EIF2B2 p.Ser171Phe (c.512C>T) is classified Pathogenic/Likely pathogenic in EIF2B2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-21). AlphaMissense: likely pathogenic (0.9851); Very rare (popmax 0.00168%, amr); Associated with leukoencephalopathy with vanishing white matter.

What condition is associated with EIF2B2 p.Ser171Phe (c.512C>T)?

EIF2B2 p.Ser171Phe (c.512C>T) is associated with leukoencephalopathy with vanishing white matter, leukoencephalopathy with vanishing white matter 2 (ClinVar).

How common is EIF2B2 p.Ser171Phe (c.512C>T) in the general population?

EIF2B2 p.Ser171Phe (c.512C>T) is very rare (popmax 0.00168%, amr) (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.Ser171Phe (c.512C>T)?

AlphaMissense predicts likely pathogenic (score 0.9851) — an in-silico prediction, not a clinical call.

EIF2B2 p.Ser171Phe

c.512C>T · rs104894428 · VCV4339

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9851 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukoencephalopathy with vanishing white matter

Computational evidence

Protein change
AlphaMissense	0.9851	likely pathogenic ✓ concordant with ClinVar · top 6% in EIF2B2
REVEL	0.95	strongly pathogenic-leaning
SaProt	LLR -15.48	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	30.0	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 0.00168% Admixed American · 1/59,642 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000831%

Overall 0.00137% 22/1,609,896 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,176
Admixed Americangrpmax	0.00168%	59,642
European (non-Finnish)	0.00161%	62,054

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser171Phe
Coding: c.512C>T
MANE Select: NM_014239
dbSNP: rs104894428
Type: single nucleotide variant
Location: chr14:75004815 (GRCh38)
Gene constraint: LOEUF 1.25 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.82 · 38 PDB
Residue 171: a UniProt-annotated variant site (in vwm2; with ovarian failure)

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

Disease context

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

Also linked: leukoencephalopathy with vanishing white matter 2

For CACH syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

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
EIF2B2 p.Gly200Val Pathogenic/Likely pathogenic ★★ same condition
EIF2B2 p.Lys273Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
EIF2B2 p.Met1Ile 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-ser171phe (accessed [today's date]).

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