Is CLCA1 p.Asp412Val (c.1235A>T) pathogenic?

CLCA1 p.Asp412Val (c.1235A>T) is classified Uncertain significance in CLCA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-08). AlphaMissense: likely pathogenic (0.8837); Very rare (popmax 0.00267%, afr).

How common is CLCA1 p.Asp412Val (c.1235A>T) in the general population?

CLCA1 p.Asp412Val (c.1235A>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CLCA1 p.Asp412Val (c.1235A>T)?

AlphaMissense predicts likely pathogenic (score 0.8837) — an in-silico prediction, not a clinical call.

CLCA1 p.Asp412Val

c.1235A>T · VCV3833713

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8837 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8837	likely pathogenic · top 5% in CLCA1
REVEL	0.572	indeterminate
SaProt	LLR -14.85	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 31 kb · p 0.017 · regional, not allelic
Overall
CADD	24.9	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 0.00267% African / African-American · 2/74,910 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,982 alleles · very rare exomes 0/1,461,824 · genomes 2/152,158 · 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.Asp412Val
Coding: c.1235A>T
MANE Select: NM_001285
Type: single nucleotide variant
Location: chr1:86489048 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.40 · 2 PDB
Residue 412: the vwfa domain

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

Similar variants

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
CLCA1 p.Ala442Ser 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-asp412val (accessed [today's date]).

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