Is EHD2 p.Ala340Glu (c.1019C>A) pathogenic?

EHD2 p.Ala340Glu (c.1019C>A) is classified Uncertain significance in EHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-26). AlphaMissense: ambiguous (0.3621); Very rare (popmax 0.00458%, nfe).

How common is EHD2 p.Ala340Glu (c.1019C>A) in the general population?

EHD2 p.Ala340Glu (c.1019C>A) is very rare (popmax 0.00458%, nfe) (gnomAD).

What do computational predictors say about EHD2 p.Ala340Glu (c.1019C>A)?

AlphaMissense predicts ambiguous (score 0.3621) — an in-silico prediction, not a clinical call.

EHD2 p.Ala340Glu

c.1019C>A · rs761441836 · VCV2537088

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3621 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00458%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3621	ambiguous
REVEL	0.143	moderately benign-leaning
SaProt	LLR -6.78	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 0.52, phastCons 0.97
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00029 · regional, not allelic
Overall
CADD	21.1	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 0.00458% European (non-Finnish) · 54/1,179,468 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00321%

Overall 0.00353% 57/1,612,532 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00458%	21,842
Remaining individualsnot grpmax-eligible	0.0032%	31,218
Admixed American	0.00167%	59,732

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: EHD2
Protein: p.Ala340Glu
Coding: c.1019C>A
MANE Select: NM_014601
dbSNP: rs761441836
Type: single nucleotide variant
Location: chr19:47736472 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.15
Residue 340: the 'mediates membrane-binding' region

Full EHD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EHD2 p.Ala161Thr Uncertain significance ★ ⚠ same type
EHD2 p.Ala308Thr Uncertain significance ★ ⚠ same type
EHD2 p.Ala365Val Uncertain significance ★ ⚠ same type
EHD2 p.Ala391Pro Uncertain significance ★ ⚠ same type
EHD2 p.Ala413Thr Uncertain significance ★ ⚠ same type
EHD2 p.Ala442Asp Uncertain significance ★ ⚠ same type
EHD2 p.Ala461Val Uncertain significance ★ ⚠ same type
EHD2 p.Ala524Asp 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/ehd2-p-ala340glu (accessed [today's date]).

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