HCLS1

Chr 3

hematopoietic cell-specific Lyn substrate 1

Also known as: CTTNL, HS1, lckBP1, p75

NCBI Gene: 3059 ENSG00000180353 UniProt: P14317 OMIM: 601306

HCLS1 encodes a signaling adaptor protein that functions as a substrate for antigen receptor-coupled tyrosine kinases and regulates antigen receptor signaling in lymphoid cells. The gene is extremely tolerant to loss-of-function variants (pLI near 0), indicating that complete loss of function is likely compatible with normal development. No specific Mendelian diseases have been established for HCLS1 mutations in current clinical practice.

OMIM ResearchSummary from RefSeq, UniProt

Enables RNA polymerase II-specific DNA-binding transcription factor binding activity; protein kinase binding activity; and signaling adaptor activity. Involved in several processes, including granulocyte colony-stimulating factor signaling pathway; positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; and positive regulation of protein import into nucleus. Located in cytosol; nucleus; and plasma membrane. Part of transcription regulator complex. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.73

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.73LOEUF

pLI 0.000

Z-score 2.72

OE 0.48 (0.32–0.73)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.05Z-score

OE missense 1.01 (0.92–1.11)

283 obs / 280.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.48 (0.32–0.73)

0≤0.351.4

Missense OE?1.01 (0.92–1.11)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 15 / 31.5Missense obs/exp: 283 / 280.5Syn Z: 0.47

Background carrier burden — how many people carry a rare variant somewhere in HCLS1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 56

645 rare PASS variants

Rare truncating (LoF)

1 in 900

85 rare PASS variants

Rare synonymous (reference)

1 in 150

231 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HCLS1. 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 110	1 in 450
South Asian	~43k	1 in 71	1 in 880
Remaining (unassigned)	~30k	1 in 58	1 in 1,000
European (Finnish)	~27k	1 in 130	≈ 1 in 27,000
Admixed American	~22k	1 in 69	1 in 930
African / African American	~21k	1 in 61	1 in 2,500
East Asian	~20k	1 in 73	1 in 1,500
Ashkenazi Jewish	~13k	1 in 570	none seen
Middle Eastern	~2,884	1 in 53	≈ 1 in 1,400

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.