Is EHD4 p.Ser532Pro (c.1594T>C) pathogenic?

EHD4 p.Ser532Pro (c.1594T>C) is classified Uncertain significance in EHD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: ambiguous (0.3527); Very rare (popmax 0.00268%, afr).

How common is EHD4 p.Ser532Pro (c.1594T>C) in the general population?

EHD4 p.Ser532Pro (c.1594T>C) is very rare (popmax 0.00268%, afr) (gnomAD).

What do computational predictors say about EHD4 p.Ser532Pro (c.1594T>C)?

AlphaMissense predicts ambiguous (score 0.3527) — an in-silico prediction, not a clinical call.

EHD4 p.Ser532Pro

c.1594T>C · VCV4663520

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3527 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Computational evidence

Protein change
AlphaMissense	0.3527	ambiguous
REVEL	0.328	indeterminate
SaProt	LLR -13.15	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 72 kb · p 0.00019 · 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 0.00268% African / African-American · 2/74,724 alleles

Filtering AF 0.000804% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00112% 18/1,601,592 alleles · very rare exomes 16/1,449,846 · genomes 2/151,746 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00268%	37,362
European (non-Finnish)	0.00136%	73,649

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.Ser532Pro
Coding: c.1594T>C
MANE Select: NM_139265
Type: single nucleotide variant
Location: chr15:41900677 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.19
Residue 532: the eh domain

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

Similar variants

EHD4 p.Ser532Leu Uncertain significance ★ ⚠ same residue
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

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-ser532pro (accessed [today's date]).

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