Is EIF2AK3 p.Arg34Pro (c.101G>C) pathogenic?

EIF2AK3 p.Arg34Pro (c.101G>C) is classified Uncertain significance in EIF2AK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-12). AlphaMissense: likely benign (0.0814); Ultra-rare (popmax 0.0122%, eas); Associated with Wolcott-Rallison syndrome.

What condition is associated with EIF2AK3 p.Arg34Pro (c.101G>C)?

EIF2AK3 p.Arg34Pro (c.101G>C) is associated with Wolcott-Rallison syndrome (ClinVar).

How common is EIF2AK3 p.Arg34Pro (c.101G>C) in the general population?

EIF2AK3 p.Arg34Pro (c.101G>C) is ultra-rare (popmax 0.0122%, eas) (gnomAD).

How is Wolcott-Rallison syndrome inherited?

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

What do computational predictors say about EIF2AK3 p.Arg34Pro (c.101G>C)?

AlphaMissense predicts likely benign (score 0.0814) — an in-silico prediction, not a clinical call.

EIF2AK3 p.Arg34Pro

c.101G>C · VCV3587019

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0814 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Wolcott-Rallison syndrome

Computational evidence

Protein change
AlphaMissense	0.0814	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -6.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.81	GERP -1.8, phastCons 0.017
Regional constraint	o/e 1.08	unconstrained · MANE · 13 kb · p 0.3 · regional, not allelic
Overall
CADD	11.31	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 0.0122% East Asian · 4/32,832 alleles

Filtering AF 0.00414% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.000278% 4/1,440,402 alleles · ultra-rare exomes 4/1,288,730 · genomes 0/151,672 · joint denominator

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: EIF2AK3
Protein: p.Arg34Pro
Coding: c.101G>C
MANE Select: NM_004836
Type: single nucleotide variant
Location: chr2:88627174 (GRCh38)
Gene constraint: LOEUF 0.606 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 59.85 · 15 PDB

Full EIF2AK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Wolcott-Rallison syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Wolcott-Rallison syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

EIF2AK3 p.Arg34His Uncertain significance ★ ⚠ same residue
EIF2AK3 c.1306+1G>A Likely pathogenic ★★ same condition
EIF2AK3 c.1306+1G>C Likely pathogenic ★★ same condition
EIF2AK3 p.Arg588Ter Pathogenic/Likely pathogenic ★★ same condition
EIF2AK3 p.Arg633Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
EIF2AK3 p.Arg638Ter Pathogenic ★★ same condition
EIF2AK3 p.Gln398Ter Pathogenic ★★ same condition
EIF2AK3 p.Glu710Ter 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/eif2ak3-p-arg34pro (accessed [today's date]).

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