Is EHD1 p.Ala99Ser (c.295G>T) pathogenic?

EHD1 p.Ala99Ser (c.295G>T) is classified Uncertain significance in EHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-12). AlphaMissense: ambiguous (0.3883); Ultra-rare (popmax 0.0331%, mid).

How common is EHD1 p.Ala99Ser (c.295G>T) in the general population?

EHD1 p.Ala99Ser (c.295G>T) is ultra-rare (popmax 0.0331%, mid) (gnomAD).

What do computational predictors say about EHD1 p.Ala99Ser (c.295G>T)?

AlphaMissense predicts ambiguous (score 0.3883) — an in-silico prediction, not a clinical call.

EHD1 p.Ala99Ser

c.295G>T · VCV4247519

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3883 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3883	ambiguous
REVEL	0.747	pathogenic-leaning
SaProt	LLR -10.66	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 5.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 24 kb · p 2.1e-14 · regional, not allelic
Overall
CADD	27.3	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 0.0331% Middle Eastern · 2/6,042 alleles

Filtering AF 0.00584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00243%

Overall 0.000413% 6/1,452,988 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0331%	3,021
Remaining individualsnot grpmax-eligible	0.00161%	62,020
European (non-Finnish)	0.000256%	391,048

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: EHD1
Protein: p.Ala99Ser
Coding: c.295G>T
MANE Select: NM_006795
Type: single nucleotide variant
Location: chr11:64878170 (GRCh38)
Gene constraint: LOEUF 0.676 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 89.65 · 5 PDB
Residue 99: the dynamin-type g domain

Full EHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EHD1 p.Ala273= Benign ★★ same type
EHD1 p.Gly464= Benign ★★ same type
EHD1 p.Leu114= Benign ★★ same type
EHD1 p.Leu187= Benign ★★ same type
EHD1 p.Ala304Gly Uncertain significance ★ ⚠ same type
EHD1 p.Ala308Thr Uncertain significance ★ ⚠ same type
EHD1 p.Ala373Val Uncertain significance ★ ⚠ same type
EHD1 p.Ala413Val 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/ehd1-p-ala99ser (accessed [today's date]).

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