Is EHD4 p.Pro250Thr (c.748C>A) pathogenic?

EHD4 p.Pro250Thr (c.748C>A) is classified Uncertain significance in EHD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-26). AlphaMissense: likely pathogenic (0.8681); Very rare (popmax 0.00502%, amr).

How common is EHD4 p.Pro250Thr (c.748C>A) in the general population?

EHD4 p.Pro250Thr (c.748C>A) is very rare (popmax 0.00502%, amr) (gnomAD).

What do computational predictors say about EHD4 p.Pro250Thr (c.748C>A)?

AlphaMissense predicts likely pathogenic (score 0.8681) — an in-silico prediction, not a clinical call.

EHD4 p.Pro250Thr

c.748C>A · VCV3274892

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8681 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00502%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8681	likely pathogenic
REVEL	0.749	pathogenic-leaning
SaProt	LLR -14.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 72 kb · p 0.00019 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.00502% Admixed American · 3/59,788 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000669%

Overall 0.000745% 12/1,611,530 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00502%	19,929
Remaining individualsnot grpmax-eligible	0.00321%	31,190
European (non-Finnish)	0.000594%	168,357

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: EHD4
Protein: p.Pro250Thr
Coding: c.748C>A
MANE Select: NM_139265
Type: single nucleotide variant
Location: chr15:41919386 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.19
Residue 250: the dynamin-type g domain

Full EHD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EHD4 p.Ala194Gly Uncertain significance ★ ⚠ same type
EHD4 p.Ala276Thr Uncertain significance ★ ⚠ same type
EHD4 p.Ala304Val Uncertain significance ★ ⚠ same type
EHD4 p.Ala437Thr Uncertain significance ★ ⚠ same type
EHD4 p.Ala505Pro Uncertain significance ★ ⚠ same type
EHD4 p.Ala9Glu Uncertain significance ★ ⚠ same type
EHD4 p.Arg14Ser Uncertain significance ★ ⚠ same type
EHD4 p.Arg211Trp 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/ehd4-p-pro250thr (accessed [today's date]).

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