Is EIF2AK2 p.Ser97Phe (c.290C>T) pathogenic?

EIF2AK2 p.Ser97Phe (c.290C>T) is classified Uncertain significance in EIF2AK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-12-18). AlphaMissense: likely benign (0.124); Absent from gnomAD v4.1; Associated with Developmental regression.

What condition is associated with EIF2AK2 p.Ser97Phe (c.290C>T)?

EIF2AK2 p.Ser97Phe (c.290C>T) is associated with Developmental regression, leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (ClinVar).

How common is EIF2AK2 p.Ser97Phe (c.290C>T) in the general population?

EIF2AK2 p.Ser97Phe (c.290C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EIF2AK2 p.Ser97Phe (c.290C>T)?

AlphaMissense predicts likely benign (score 0.124) — an in-silico prediction, not a clinical call.

EIF2AK2 p.Ser97Phe

c.290C>T · rs1573031939 · VCV813275

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.124 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Developmental regression

Computational evidence

Protein change
AlphaMissense	0.124	likely benign
REVEL	0.251	benign-leaning
SaProt	LLR -8.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.3	GERP -1.8
Regional constraint	o/e 1.08	unconstrained · MANE · 9,886 bp · p 0.24 · regional, not allelic
Overall
CADD	0.932	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: EIF2AK2
Protein: p.Ser97Phe
Coding: c.290C>T
MANE Select: NM_001135651
dbSNP: rs1573031939
Type: single nucleotide variant
Location: chr2:37141652 (GRCh38)
Gene constraint: LOEUF 0.735 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.52 · 12 PDB
Residue 97: a UniProt-annotated variant site (in leuden; uncertain significance); the '(microbial infection) interaction with hcv ns5a' region

Full EIF2AK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Developmental regression — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome

Similar variants

EIF2AK2 p.Ser97Thr Uncertain significance ★ ⚠ same residue
EIF2AK2 p.Ala109Val Uncertain significance ★★ same condition
EIF2AK2 p.Arg499Gln Uncertain significance ★★ ⚠ same condition
EIF2AK2 p.Tyr133Phe Uncertain significance ★★ ⚠ same condition
EIF2AK2 c.1533+2T>A Uncertain significance ★ same condition
EIF2AK2 p.Ala109Ser Conflicting classifications of pathogenicity ★ ⚠ same condition
EIF2AK2 p.Arg297His Uncertain significance ★ ⚠ same condition
EIF2AK2 p.Asn324Ser Conflicting classifications of pathogenicity ★ ⚠ 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/eif2ak2-p-ser97phe (accessed [today's date]).

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