Is CLCA4 p.Ala59Val (c.176C>T) pathogenic?

CLCA4 p.Ala59Val (c.176C>T) is classified Uncertain significance in CLCA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-29). AlphaMissense: likely pathogenic (0.7209); Very rare (popmax 0.00229%, sas).

How common is CLCA4 p.Ala59Val (c.176C>T) in the general population?

CLCA4 p.Ala59Val (c.176C>T) is very rare (popmax 0.00229%, sas) (gnomAD).

What do computational predictors say about CLCA4 p.Ala59Val (c.176C>T)?

AlphaMissense predicts likely pathogenic (score 0.7209) — an in-silico prediction, not a clinical call.

CLCA4 p.Ala59Val

c.176C>T · rs2524672224 · VCV3145374

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7209 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7209	likely pathogenic · top 10% in CLCA4
REVEL	0.393	indeterminate
SaProt	LLR -14.65	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 33 kb · p 0.26 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00229% South Asian · 2/87,266 alleles

Filtering AF 0.00038% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000142%

Overall 0.000188% 3/1,598,616 alleles · very rare exomes 3/1,446,366 · genomes 0/152,250 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00229%	43,633
Remaining individualsnot grpmax-eligible	0.00161%	61,986

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: CLCA4
Protein: p.Ala59Val
Coding: c.176C>T
MANE Select: NM_012128
dbSNP: rs2524672224
Type: single nucleotide variant
Location: chr1:86559948 (GRCh38)
Gene constraint: LOEUF 1.078 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.48
Residue 59: the 'metalloprotease domain' region

Full CLCA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCA4 p.Asp510Gly Uncertain significance ★★ ⚠ same type
CLCA4 p.Gln485Ter Uncertain significance ★★ same type
CLCA4 p.Arg113= Benign/Likely benign ★★ same type
CLCA4 p.Ala235Thr Uncertain significance ★ ⚠ same type
CLCA4 p.Ala353Val Uncertain significance ★ same type
CLCA4 p.Ala431Thr Uncertain significance ★ ⚠ same type
CLCA4 p.Ala431Val Uncertain significance ★ ⚠ same type
CLCA4 p.Ala437Gly 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/clca4-p-ala59val (accessed [today's date]).

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