Is EHD3 p.Asp459Glu (c.1377T>G) pathogenic?

EHD3 p.Asp459Glu (c.1377T>G) is classified Uncertain significance in EHD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-19). AlphaMissense: likely benign (0.1363); Absent from gnomAD v4.1.

How common is EHD3 p.Asp459Glu (c.1377T>G) in the general population?

EHD3 p.Asp459Glu (c.1377T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EHD3 p.Asp459Glu (c.1377T>G)?

AlphaMissense predicts likely benign (score 0.1363) — an in-silico prediction, not a clinical call.

EHD3 p.Asp459Glu

c.1377T>G · VCV4016979

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1363 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1363	likely benign
REVEL	0.219	benign-leaning
SaProt	LLR -7.55	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 -11
Regional constraint	o/e 0.93	unconstrained · MANE · 5,876 bp · p 0.16 · regional, not allelic
Overall
CADD	5.457	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: EHD3
Protein: p.Asp459Glu
Coding: c.1377T>G
MANE Select: NM_014600
Type: single nucleotide variant
Location: chr2:31266473 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI 0.61 (gnomAD)
Structure: AlphaFold pLDDT 88.56
Residue 459: the eh domain

Full EHD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EHD3 c.502+9C>T Benign ★★ same type
EHD3 p.Arg215= Benign ★★ same type
EHD3 p.Ala127Thr Uncertain significance ★ ⚠ same type
EHD3 p.Ala131Thr Uncertain significance ★ ⚠ same type
EHD3 p.Ala290Val Uncertain significance ★ ⚠ same type
EHD3 p.Ala413Ser Uncertain significance ★ ⚠ same type
EHD3 p.Ala437Thr Uncertain significance ★ ⚠ same type
EHD3 p.Ala99Val 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/ehd3-p-asp459glu (accessed [today's date]).

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