Is CLCA2 p.Ala334Gly (c.1001C>G) pathogenic?

CLCA2 p.Ala334Gly (c.1001C>G) is classified Uncertain significance in CLCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-22). AlphaMissense: likely benign (0.2017); Rare (popmax 0.148%, afr).

How common is CLCA2 p.Ala334Gly (c.1001C>G) in the general population?

CLCA2 p.Ala334Gly (c.1001C>G) is rare (popmax 0.148%, afr) (gnomAD).

What do computational predictors say about CLCA2 p.Ala334Gly (c.1001C>G)?

AlphaMissense predicts likely benign (score 0.2017) — an in-silico prediction, not a clinical call.

CLCA2 p.Ala334Gly

c.1001C>G · rs148036152 · VCV2380833

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2017 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.148%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2017	likely benign
REVEL	0.42	indeterminate
SaProt	LLR -8.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 31 kb · p 0.29 · regional, not allelic
Overall
CADD	25.1	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 0.148% African / African-American · 111/75,024 alleles

Filtering AF 0.126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.117%

Overall 0.00843% 136/1,614,058 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.148%	676
Admixed American	0.0217%	4,616
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.016%	6,250
European (non-Finnish)	8.47e-05%	1,179,970

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.Ala334Gly
Coding: c.1001C>G
MANE Select: NM_006536
dbSNP: rs148036152
Type: single nucleotide variant
Location: chr1:86438904 (GRCh38)
Gene constraint: LOEUF 1.144 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.87
Residue 334: the vwfa domain

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

Similar variants

CLCA2 p.Ala334Asp 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-ala334gly (accessed [today's date]).

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