Is EHD3 p.Val440Met (c.1318G>A) pathogenic?

EHD3 p.Val440Met (c.1318G>A) is classified Uncertain significance in EHD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-16). AlphaMissense: ambiguous (0.4767); Very rare (popmax 0.000254%, nfe).

How common is EHD3 p.Val440Met (c.1318G>A) in the general population?

EHD3 p.Val440Met (c.1318G>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about EHD3 p.Val440Met (c.1318G>A)?

AlphaMissense predicts ambiguous (score 0.4767) — an in-silico prediction, not a clinical call.

EHD3 p.Val440Met

c.1318G>A · VCV4247546

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4767 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4767	ambiguous
REVEL	0.165	moderately benign-leaning
SaProt	LLR -12.10	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 5,876 bp · p 0.16 · regional, not allelic
Overall
CADD	24.3	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

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,944 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,776 alleles · very rare

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: EHD3
Protein: p.Val440Met
Coding: c.1318G>A
MANE Select: NM_014600
Type: single nucleotide variant
Location: chr2:31266414 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI 0.61 (gnomAD)
Structure: AlphaFold pLDDT 88.56

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-val440met (accessed [today's date]).

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