Is EHD3 p.Arg473Cys (c.1417C>T) pathogenic?

EHD3 p.Arg473Cys (c.1417C>T) is classified Uncertain significance in EHD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: likely benign (0.1951); Ultra-rare (popmax 0.0164%, mid).

How common is EHD3 p.Arg473Cys (c.1417C>T) in the general population?

EHD3 p.Arg473Cys (c.1417C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about EHD3 p.Arg473Cys (c.1417C>T)?

AlphaMissense predicts likely benign (score 0.1951) — an in-silico prediction, not a clinical call.

EHD3 p.Arg473Cys

c.1417C>T · VCV4663509

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1951 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1951	likely benign
REVEL	0.296	indeterminate
SaProt	LLR -12.20	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 5,876 bp · p 0.16 · regional, not allelic
Overall
CADD	32.0	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.00192% 31/1,613,998 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00801%	12,483
East Asian	0.00223%	44,880
European (non-Finnish)	0.00178%	56,192
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,082

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.Arg473Cys
Coding: c.1417C>T
MANE Select: NM_014600
Type: single nucleotide variant
Location: chr2:31266513 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI 0.61 (gnomAD)
Structure: AlphaFold pLDDT 88.56
Residue 473: the eh domain

Full EHD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EHD3 p.Arg473His Uncertain significance ★ ⚠ same residue
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

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-arg473cys (accessed [today's date]).

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