Is EHD4 p.Lys308Arg (c.923A>G) pathogenic?

EHD4 p.Lys308Arg (c.923A>G) is classified Uncertain significance in EHD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-18). AlphaMissense: likely benign (0.1462); Ultra-rare (popmax 0.0453%, afr).

How common is EHD4 p.Lys308Arg (c.923A>G) in the general population?

EHD4 p.Lys308Arg (c.923A>G) is ultra-rare (popmax 0.0453%, afr) (gnomAD).

What do computational predictors say about EHD4 p.Lys308Arg (c.923A>G)?

AlphaMissense predicts likely benign (score 0.1462) — an in-silico prediction, not a clinical call.

EHD4 p.Lys308Arg

c.923A>G · VCV3507410

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1462 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0453%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1462	likely benign
REVEL	0.721	pathogenic-leaning
SaProt	LLR -3.48	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 72 kb · p 0.00019 · regional, not allelic
Overall
CADD	25.3	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 0.0453% African / African-American · 34/75,070 alleles

Filtering AF 0.0333% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0291%

Overall 0.00273% 44/1,613,750 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0453%	2,208
Admixed American	0.0117%	8,576
Remaining individualsnot grpmax-eligible	0.0016%	62,494
South Asian	0.0011%	91,080
European (non-Finnish)	8.47e-05%	1,180,030

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.Lys308Arg
Coding: c.923A>G
MANE Select: NM_139265
Type: single nucleotide variant
Location: chr15:41919211 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.19

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-lys308arg (accessed [today's date]).

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