Is EIF2D p.Leu124Pro (c.371T>C) pathogenic?

EIF2D p.Leu124Pro (c.371T>C) is classified Uncertain significance in EIF2D (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: ambiguous (0.5204); Absent from gnomAD v4.1.

How common is EIF2D p.Leu124Pro (c.371T>C) in the general population?

EIF2D p.Leu124Pro (c.371T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EIF2D p.Leu124Pro (c.371T>C)?

AlphaMissense predicts ambiguous (score 0.5204) — an in-silico prediction, not a clinical call.

EIF2D p.Leu124Pro

c.371T>C · VCV4247734

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5204 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.5204	ambiguous
REVEL	0.496	indeterminate
SaProt	LLR -9.84	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 2.2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 21 kb · p 6.2e-07 · regional, not allelic
Overall
CADD	28.0	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

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: EIF2D
Protein: p.Leu124Pro
Coding: c.371T>C
MANE Select: NM_006893
Type: single nucleotide variant
Location: chr1:206608287 (GRCh38)
Gene constraint: LOEUF 0.862 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.23 · 3 PDB
Residue 124: the pua domain

Full EIF2D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EIF2D p.Leu124Val Uncertain significance ★ ⚠ same residue
EIF2D p.Ala149Ser Uncertain significance ★ ⚠ same type
EIF2D p.Ala150Val Uncertain significance ★ ⚠ same type
EIF2D p.Ala24Thr Uncertain significance ★ ⚠ same type
EIF2D p.Ala499Val Uncertain significance ★ ⚠ same type
EIF2D p.Arg20Ser Uncertain significance ★ ⚠ same type
EIF2D p.Arg508Gln Uncertain significance ★ ⚠ same type
EIF2D p.Arg527Gln Uncertain significance ★ ⚠ same type

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/eif2d-p-leu124pro (accessed [today's date]).

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