Is CLCA2 p.Arg158Pro (c.473G>C) pathogenic?

CLCA2 p.Arg158Pro (c.473G>C) is classified Uncertain significance in CLCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-06). AlphaMissense: likely benign (0.2577); Ultra-rare (popmax 0.0157%, nfe).

How common is CLCA2 p.Arg158Pro (c.473G>C) in the general population?

CLCA2 p.Arg158Pro (c.473G>C) is ultra-rare (popmax 0.0157%, nfe) (gnomAD).

What do computational predictors say about CLCA2 p.Arg158Pro (c.473G>C)?

AlphaMissense predicts likely benign (score 0.2577) — an in-silico prediction, not a clinical call.

CLCA2 p.Arg158Pro

c.473G>C · rs143721621 · VCV2509774

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2577 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0157%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2577	likely benign
REVEL	0.447	indeterminate
SaProt	LLR -10.43	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 31 kb · p 0.29 · regional, not allelic
Overall
CADD	33.0	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 0.0157% European (non-Finnish) · 185/1,179,212 alleles

Filtering AF 0.0138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0131%

Overall 0.0118% 191/1,612,552 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0157%	6,374
Remaining individualsnot grpmax-eligible	0.0048%	20,812
Finnishnot grpmax-eligible	0.00313%	31,955
Admixed American	0.00167%	59,862

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: CLCA2
Protein: p.Arg158Pro
Coding: c.473G>C
MANE Select: NM_006536
dbSNP: rs143721621
Type: single nucleotide variant
Location: chr1:86428566 (GRCh38)
Gene constraint: LOEUF 1.144 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.87
Residue 158: the 'metalloprotease domain' region

Full CLCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCA2 p.Arg158Gln Uncertain significance ★ ⚠ same residue
CLCA2 p.Leu169Phe Uncertain significance ★★ ⚠ same type
CLCA2 p.Gln842= Benign ★★ same type
CLCA2 p.Thr845= Benign ★★ same type
CLCA2 p.Tyr155= Benign ★★ same type
CLCA2 c.475+2T>A Uncertain significance ★ same type
CLCA2 p.Ala109Val Uncertain significance ★ same type
CLCA2 p.Ala238Val 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/clca2-p-arg158pro (accessed [today's date]).

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