CRKL

Chr 22

CRK like proto-oncogene, adaptor protein

NCBI Gene: 1399 ENSG00000099942 UniProt: P46109 OMIM: 602007

The protein is an adaptor kinase containing SH2 and SH3 domains that activates RAS and JUN kinase signaling pathways and mediates intracellular signal transduction. Mutations cause autosomal dominant developmental disorders including intellectual disability, seizures, and craniofacial abnormalities, often as part of 22q11.2 deletion syndrome. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.64), suggesting some tolerance to haploinsufficiency.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein kinase containing SH2 and SH3 (src homology) domains which has been shown to activate the RAS and JUN kinase signaling pathways and transform fibroblasts in a RAS-dependent fashion. It is a substrate of the BCR-ABL tyrosine kinase, plays a role in fibroblast transformation by BCR-ABL, and may be oncogenic.[provided by RefSeq, Jan 2009]

OMIM ResearchGenerating clinical summary…

LOEUF 0.64

Clinical Summary— CRKL

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Gene-Disease Validity (ClinGen)

congenital heart disease · UDNo Known Disease Relationship

No known disease relationship

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.20) despite low pLI — interpret in context.

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ClinVar Variants

28 VUS of 55 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.64LOEUF

pLI 0.446

Z-score 2.31

OE 0.20 (0.08–0.64)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.94Z-score

OE missense 0.59 (0.50–0.69)

105 obs / 177.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.20 (0.08–0.64)

0≤0.351.4

Missense OE?0.59 (0.50–0.69)

0≤0.61.4

Synonymous OE?1.30

0≤1.21.6

LoF obs/exp: 2 / 9.8Missense obs/exp: 105 / 177.7Syn Z: -2.03

ClinVar Variant Classifications

55 submitted variants in ClinVar

ClinVar

Classification Summary

VUS28

Likely Benign22

Benign3

Conflicting1

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	3	22	3	0	28
Likely Benign	0	0	3	19	22
Benign	0	1	1	1	3
Conflicting	—				1
Total	3	23	7	20	54

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

363 pathogenic / likely-pathogenic (of 429) ClinVar copy-number / structural variants overlap CRKL — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →