Is EHD3 p.Ala99Val (c.296C>T) pathogenic?

EHD3 p.Ala99Val (c.296C>T) is classified Uncertain significance in EHD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: ambiguous (0.4054); Very rare (popmax 0.00329%, sas).

How common is EHD3 p.Ala99Val (c.296C>T) in the general population?

EHD3 p.Ala99Val (c.296C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about EHD3 p.Ala99Val (c.296C>T)?

AlphaMissense predicts ambiguous (score 0.4054) — an in-silico prediction, not a clinical call.

EHD3 p.Ala99Val

c.296C>T · VCV4247538

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4054 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4054	ambiguous
REVEL	0.775	moderately pathogenic-leaning
SaProt	LLR -10.61	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 26 kb · p 0.0018 · regional, not allelic
Overall
CADD	25.1	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 0.00329% South Asian · 3/91,084 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000479% 7/1,461,850 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,361
East Asian	0.00223%	44,870
European (non-Finnish)	0.000254%	393,342

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.Ala99Val
Coding: c.296C>T
MANE Select: NM_014600
Type: single nucleotide variant
Location: chr2:31244342 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI 0.61 (gnomAD)
Structure: AlphaFold pLDDT 88.56
Residue 99: the dynamin-type g 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.Arg12Gly 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-ala99val (accessed [today's date]).

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