Is CLCA1 p.Arg686Pro (c.2057G>C) pathogenic?

CLCA1 p.Arg686Pro (c.2057G>C) is classified Uncertain significance in CLCA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-02). AlphaMissense: likely benign (0.1441); Ultra-rare (popmax 0.0133%, amr).

How common is CLCA1 p.Arg686Pro (c.2057G>C) in the general population?

CLCA1 p.Arg686Pro (c.2057G>C) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about CLCA1 p.Arg686Pro (c.2057G>C)?

AlphaMissense predicts likely benign (score 0.1441) — an in-silico prediction, not a clinical call.

CLCA1 p.Arg686Pro

c.2057G>C · VCV4229394

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1441 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1441	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -4.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.011	GERP -3.7
Regional constraint	o/e 0.93	unconstrained · MANE · 31 kb · p 0.017 · regional, not allelic
Overall
CADD	1.901	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 0.0133% Admixed American · 8/60,000 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.000496% 8/1,613,982 alleles · ultra-rare exomes 7/1,461,828 · genomes 1/152,154 · joint denominator

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: CLCA1
Protein: p.Arg686Pro
Coding: c.2057G>C
MANE Select: NM_001285
Type: single nucleotide variant
Location: chr1:86495619 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.40 · 2 PDB

Full CLCA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCA1 p.Arg686Gln Likely benign ★ same residue
CLCA1 c.2113+8A>G Benign ★★ same type
CLCA1 p.Asn682Lys Benign ★★ same type
CLCA1 p.Tyr661His Benign ★★ ⚠ same type
CLCA1 p.Val609Ile Benign ★★ same type
CLCA1 p.Ala189Pro Uncertain significance ★ ⚠ same type
CLCA1 p.Ala436Thr Uncertain significance ★ ⚠ same type
CLCA1 p.Ala441Val 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/clca1-p-arg686pro (accessed [today's date]).

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