Is CLCA1 p.Ala559Val (c.1676C>T) pathogenic?

CLCA1 p.Ala559Val (c.1676C>T) is classified Uncertain significance in CLCA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-20). AlphaMissense: ambiguous (0.3735); Very rare (popmax 0.0011%, sas).

How common is CLCA1 p.Ala559Val (c.1676C>T) in the general population?

CLCA1 p.Ala559Val (c.1676C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CLCA1 p.Ala559Val (c.1676C>T)?

AlphaMissense predicts ambiguous (score 0.3735) — an in-silico prediction, not a clinical call.

CLCA1 p.Ala559Val

c.1676C>T · rs1648194887 · VCV3145339

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3735 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Computational evidence

Protein change
AlphaMissense	0.3735	ambiguous
REVEL	0.4	indeterminate
SaProt	LLR -10.06	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.87 · evaluated, not missing
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	25.4	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 0.0011% South Asian · 1/91,020 alleles

Overall 0.000124% 2/1,611,228 alleles · very rare exomes 2/1,459,002 · genomes 0/152,226 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,020
European (non-Finnish)	8.49e-05%	1,177,428

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.Ala559Val
Coding: c.1676C>T
MANE Select: NM_001285
dbSNP: rs1648194887
Type: single nucleotide variant
Location: chr1:86493595 (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-ala559val (accessed [today's date]).

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