CLCA1

Chr 1

chloride channel accessory 1

Also known as: CACC, CACC1, CLCRG1, CaCC-1, GOB5, hCLCA1, hCaCC-1

NCBI Gene: 1179 ENSG00000016490 UniProt: A8K7I4 OMIM: 603906

This protein is a calcium-activated chloride channel that regulates mucus production and secretion by goblet cells in the intestine and respiratory tract. CLCA1 is extremely intolerant to loss-of-function variants (pLI near 1.0), but no definitive Mendelian disease associations have been established in humans to date. The gene is primarily studied in the context of respiratory conditions like asthma and cystic fibrosis, but causative mutations for pediatric neurogenetic disorders have not been reported.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the calcium sensitive chloride conductance protein family. To date, all members of this gene family map to the same region on chromosome 1p31-p22 and share a high degree of homology in size, sequence, and predicted structure, but differ significantly in their tissue distributions. The encoded protein is expressed as a precursor protein that is processed into two cell-surface-associated subunits, although the site at which the precursor is cleaved has not been precisely determined. The encoded protein may be involved in mediating calcium-activated chloride conductance in the intestine. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.72

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.72LOEUF

pLI 0.000

Z-score 2.99

OE 0.50 (0.35–0.72)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.71Z-score

OE missense 0.91 (0.84–0.98)

449 obs / 493.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.50 (0.35–0.72)

0≤0.351.4

Missense OE?0.91 (0.84–0.98)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 21 / 41.9Missense obs/exp: 449 / 493.1Syn Z: -0.55

Background carrier burden — how many people carry a rare variant somewhere in CLCA1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 57

1,107 rare PASS variants

Rare truncating (LoF)

1 in 990

145 rare PASS variants

Rare synonymous (reference)

1 in 140

426 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CLCA1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 72	1 in 1,200
South Asian	~43k	1 in 51	1 in 640
Remaining (unassigned)	~30k	1 in 52	1 in 580
European (Finnish)	~27k	1 in 160	1 in 3,800
Admixed American	~22k	1 in 45	1 in 400
African / African American	~21k	1 in 57	1 in 740
East Asian	~20k	1 in 61	1 in 450
Ashkenazi Jewish	~13k	1 in 870	1 in 1,300
Middle Eastern	~2,884	1 in 46	1 in 400

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 12 of 14 coding exons well covered in gnomAD exomes; exons 2, 4 marginal. Genomes: all 14.? see exons ↓