Is CLCA1 p.Pro534Ser (c.1600C>T) pathogenic?

CLCA1 p.Pro534Ser (c.1600C>T) is classified Uncertain significance in CLCA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-14). AlphaMissense: ambiguous (0.3918); Very rare (popmax 0.01%, amr).

How common is CLCA1 p.Pro534Ser (c.1600C>T) in the general population?

CLCA1 p.Pro534Ser (c.1600C>T) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about CLCA1 p.Pro534Ser (c.1600C>T)?

AlphaMissense predicts ambiguous (score 0.3918) — an in-silico prediction, not a clinical call.

CLCA1 p.Pro534Ser

c.1600C>T · VCV3833708

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3918 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Computational evidence

Protein change
AlphaMissense	0.3918	ambiguous
REVEL	0.481	indeterminate
SaProt	LLR -7.81	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 31 kb · p 0.017 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/60,006 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00062% 10/1,614,036 alleles · very rare exomes 10/1,461,778 · genomes 0/152,258 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,001
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)	0.000254%	393,312

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.Pro534Ser
Coding: c.1600C>T
MANE Select: NM_001285
Type: single nucleotide variant
Location: chr1:86493519 (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 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-pro534ser (accessed [today's date]).

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