Is ENTHD1 p.Arg22Lys (c.65G>A) pathogenic?

ENTHD1 p.Arg22Lys (c.65G>A) is classified Uncertain significance in ENTHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). AlphaMissense: likely pathogenic (0.7728); Ultra-rare (popmax 0.0106%, amr).

How common is ENTHD1 p.Arg22Lys (c.65G>A) in the general population?

ENTHD1 p.Arg22Lys (c.65G>A) is ultra-rare (popmax 0.0106%, amr) (gnomAD).

What do computational predictors say about ENTHD1 p.Arg22Lys (c.65G>A)?

AlphaMissense predicts likely pathogenic (score 0.7728) — an in-silico prediction, not a clinical call.

ENTHD1 p.Arg22Lys

c.65G>A · VCV4018191

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7728 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0106%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7728	likely pathogenic · top 10% in ENTHD1
REVEL	0.386	indeterminate
SaProt	LLR -10.60	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 144 kb · p 0.0022 · regional, not allelic
Overall
CADD	25.2	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 0.0106% Admixed American · 6/56,480 alleles

Filtering AF 0.00461% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.000438% 7/1,599,630 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0106%	9,413
South Asian	0.00113%	88,470

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: ENTHD1
Protein: p.Arg22Lys
Coding: c.65G>A
MANE Select: NM_152512
Type: single nucleotide variant
Location: chr22:39887684 (GRCh38)
Gene constraint: LOEUF 0.928 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.58
Residue 22: the enth domain

Full ENTHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENTHD1 p.Ala112Ser Uncertain significance ★ ⚠ same type
ENTHD1 p.Ala144Gly Uncertain significance ★ ⚠ same type
ENTHD1 p.Ala170Val Uncertain significance ★ ⚠ same type
ENTHD1 p.Ala385Gly Uncertain significance ★ ⚠ same type
ENTHD1 p.Arg121Trp Uncertain significance ★ ⚠ same type
ENTHD1 p.Arg141Met Uncertain significance ★ ⚠ same type
ENTHD1 p.Arg146Gln Uncertain significance ★ ⚠ same type
ENTHD1 p.Arg160Thr 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/enthd1-p-arg22lys (accessed [today's date]).

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