C1RL

Chr 12

complement C1r subcomponent like

Also known as: C1RL1, C1RLP, C1r-LP, CLSPa

NCBI Gene: 51279 ENSG00000139178 UniProt: Q9NZP8 OMIM: 608974

The protein mediates proteolytic cleavage of haptoglobin in the endoplasmic reticulum and has predicted serine-type endopeptidase activity involved in zymogen activation. Mutations cause autosomal recessive anhaptoglobinemia, characterized by complete absence of serum haptoglobin. This gene shows very low constraint to loss-of-function variation (pLI near 0), consistent with the recessive inheritance pattern observed clinically.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable serine-type endopeptidase activity. Predicted to be involved in zymogen activation. Located in extracellular exosome and obsolete extracellular space. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.16

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.16LOEUF

pLI 0.000

Z-score 1.05

OE 0.74 (0.49–1.16)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.90Z-score

OE missense 0.85 (0.77–0.94)

243 obs / 285.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.74 (0.49–1.16)

0≤0.351.4

Missense OE?0.85 (0.77–0.94)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 14 / 18.9Missense obs/exp: 243 / 285.9Syn Z: 0.28

Background carrier burden — how many people carry a rare variant somewhere in C1RL?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 59

755 rare PASS variants

Rare truncating (LoF)

1 in 1,400

112 rare PASS variants

Rare synonymous (reference)

1 in 230

224 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for C1RL. 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 83	1 in 1,700
South Asian	~43k	1 in 57	1 in 580
Remaining (unassigned)	~30k	1 in 48	1 in 1,000
European (Finnish)	~27k	1 in 260	none seen
Admixed American	~22k	1 in 64	1 in 1,300
African / African American	~21k	1 in 69	1 in 800
East Asian	~20k	1 in 56	1 in 640
Ashkenazi Jewish	~13k	1 in 680	none seen
Middle Eastern	~2,884	1 in 93	≈ 1 in 960

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 6 coding exons well covered in gnomAD exomes and genomes.? see exons ↓