Is EHD4 p.Arg283Thr (c.848G>C) pathogenic?

EHD4 p.Arg283Thr (c.848G>C) is classified Uncertain significance in EHD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-28). AlphaMissense: likely benign (0.1348); Ultra-rare (popmax 0.0433%, amr).

How common is EHD4 p.Arg283Thr (c.848G>C) in the general population?

EHD4 p.Arg283Thr (c.848G>C) is ultra-rare (popmax 0.0433%, amr) (gnomAD).

What do computational predictors say about EHD4 p.Arg283Thr (c.848G>C)?

AlphaMissense predicts likely benign (score 0.1348) — an in-silico prediction, not a clinical call.

EHD4 p.Arg283Thr

c.848G>C · VCV4016987

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1348 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0433%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1348	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -8.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP -0.55, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 72 kb · p 0.00019 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0433% Admixed American · 26/60,038 alleles

Filtering AF 0.0303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.00273% 44/1,614,184 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0433%	2,309
Middle Eastern	0.033%	3,029
Remaining individualsnot grpmax-eligible	0.0064%	15,627
African / African-American	0.004%	25,017
European (non-Finnish)	0.000763%	131,116

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.Arg283Thr
Coding: c.848G>C
MANE Select: NM_139265
Type: single nucleotide variant
Location: chr15:41919286 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.19
Residue 283: 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-arg283thr (accessed [today's date]).

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