Is CLCA2 p.Val205Ala (c.614T>C) pathogenic?

CLCA2 p.Val205Ala (c.614T>C) is classified Uncertain significance in CLCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely benign (0.1673); Ultra-rare (popmax 0.0113%, nfe).

How common is CLCA2 p.Val205Ala (c.614T>C) in the general population?

CLCA2 p.Val205Ala (c.614T>C) is ultra-rare (popmax 0.0113%, nfe) (gnomAD).

What do computational predictors say about CLCA2 p.Val205Ala (c.614T>C)?

AlphaMissense predicts likely benign (score 0.1673) — an in-silico prediction, not a clinical call.

CLCA2 p.Val205Ala

c.614T>C · VCV4003283

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1673 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0113%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1673	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -7.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.32, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 31 kb · p 0.29 · regional, not allelic
Overall
CADD	24.2	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 0.0113% European (non-Finnish) · 133/1,179,988 alleles

Filtering AF 0.00969% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.0083% 134/1,613,866 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0113%	8,872
African / African-American	0.00133%	74,910

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.Val205Ala
Coding: c.614T>C
MANE Select: NM_006536
Type: single nucleotide variant
Location: chr1:86432398 (GRCh38)
Gene constraint: LOEUF 1.144 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.87
Residue 205: the 'metalloprotease domain' region

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

Similar variants

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
CLCA2 p.Ala262Thr 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-val205ala (accessed [today's date]).

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