Is ENKUR p.Arg174Pro (c.521G>C) pathogenic?

ENKUR p.Arg174Pro (c.521G>C) is classified Uncertain significance in ENKUR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely pathogenic (0.7199); Absent from gnomAD v4.1.

How common is ENKUR p.Arg174Pro (c.521G>C) in the general population?

ENKUR p.Arg174Pro (c.521G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ENKUR p.Arg174Pro (c.521G>C)?

AlphaMissense predicts likely pathogenic (score 0.7199) — an in-silico prediction, not a clinical call.

ENKUR p.Arg174Pro

c.521G>C · VCV4249058

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7199 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7199	likely pathogenic · top 9% in ENKUR
REVEL	0.211	benign-leaning
SaProt	LLR -14.00	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.051	GERP -3.6
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.93 · regional, not allelic
Overall
CADD	5.199	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ENKUR
Protein: p.Arg174Pro
Coding: c.521G>C
MANE Select: NM_145010
Type: single nucleotide variant
Location: chr10:24990536 (GRCh38)
Gene constraint: LOEUF 0.98 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.24 · 2 PDB
Residue 174: the enkurin domain; the 'interaction with trpc proteins' region

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

Similar variants

ENKUR p.Arg174Gly Uncertain significance ★ ⚠ same residue
ENKUR p.Arg174His Likely benign ★ ⚠ same residue
ENKUR p.Gly140Glu Uncertain significance ★★ ⚠ same type
ENKUR p.Arg161Gln Uncertain significance ★ ⚠ same type
ENKUR p.Arg226Cys Uncertain significance ★ ⚠ same type
ENKUR p.Arg80Gln Uncertain significance ★ ⚠ same type
ENKUR p.Asn12Asp Uncertain significance ★ ⚠ same type
ENKUR p.Asn12Lys 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/enkur-p-arg174pro (accessed [today's date]).

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