Is EIF2AK2 p.Asp508Ala (c.1523A>C) pathogenic?

EIF2AK2 p.Asp508Ala (c.1523A>C) is classified Uncertain significance in EIF2AK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.1435); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with EIF2AK2 p.Asp508Ala (c.1523A>C)?

EIF2AK2 p.Asp508Ala (c.1523A>C) is associated with Inborn genetic diseases (ClinVar).

How common is EIF2AK2 p.Asp508Ala (c.1523A>C) in the general population?

EIF2AK2 p.Asp508Ala (c.1523A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EIF2AK2 p.Asp508Ala (c.1523A>C)?

AlphaMissense predicts likely benign (score 0.1435) — an in-silico prediction, not a clinical call.

EIF2AK2 p.Asp508Ala

c.1523A>C · VCV4247662

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1435 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1435	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -7.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.5	GERP 0.47
Regional constraint	o/e 0.80	unconstrained · MANE · 30 kb · p 8e-05 · regional, not allelic
Overall
CADD	17.79	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.Asp508Ala
Coding: c.1523A>C
MANE Select: NM_001135651
Type: single nucleotide variant
Location: chr2:37107484 (GRCh38)
Gene constraint: LOEUF 0.735 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.52 · 12 PDB
Residue 508: the protein kinase domain; the 'interaction with traf5' region

Full EIF2AK2 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

EIF2AK2 p.Arg548Gln Uncertain significance ★★ ⚠ same condition
EIF2AK2 p.Asn230Ser Uncertain significance ★★ ⚠ same condition
EIF2AK2 p.Ile215Met Uncertain significance ★★ ⚠ same condition
EIF2AK2 p.Lys238Gln Uncertain significance ★★ ⚠ same condition
EIF2AK2 p.Met252Val Uncertain significance ★★ ⚠ same condition
EIF2AK2 p.Ser438Cys Uncertain significance ★★ ⚠ same condition
EIF2AK2 p.Ser92Tyr Uncertain significance ★★ ⚠ same condition
EIF2AK2 p.Trp377Arg 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/eif2ak2-p-asp508ala (accessed [today's date]).

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