CRKL

Chr 22

CRK like proto-oncogene, adaptor protein

NCBI Gene: 1399ENSG00000099942UniProt: P46109

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]

470
ClinVar variants
351
Pathogenic / LP
0.45
pLI score
0
Active trials
Clinical Summary— CRKL
🧬
Gene-Disease Validity (ClinGen)
congenital heart disease · UDNo Known Disease Relationship

No known disease relationship

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.20) despite low pLI — interpret in context.
📋
ClinVar Variants
351 Pathogenic / Likely Pathogenic· 89 VUS of 470 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.64LOEUF
pLI 0.446
Z-score 2.31
OE 0.20 (0.08–0.64)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.94Z-score
OE missense 0.59 (0.50–0.69)
105 obs / 177.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.20 (0.08–0.64)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.59 (0.50–0.69)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.30
0≤1.21.6
LoF obs/exp: 2 / 9.8Missense obs/exp: 105 / 177.7Syn Z: -2.03

ClinVar Variant Classifications

470 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic318
Likely Pathogenic33
VUS89
Likely Benign23
Benign4
Conflicting3
318
Pathogenic
33
Likely Pathogenic
89
VUS
23
Likely Benign
4
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
318
0
318
Likely Pathogenic
0
0
33
0
33
VUS
3
22
64
0
89
Likely Benign
0
0
4
19
23
Benign
0
1
2
1
4
Conflicting
—3
Total32342120470

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

View in ClinVar →

Protein Context — Lollipop Plot

CRKL · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CRKL-related bladder exstrophy plus

limited
ADUndeterminedIncreased Gene Product Level
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
CRKL dictates anti-PD-1 resistance by mediating tumor-associated neutrophil infiltration in hepatocellular carcinoma.
Xie P et al.·J Hepatol
2024
Central 22q11.2 deletions.
Rump P et al.·Am J Med Genet A
2014
Hypoxia-induced up-regulation of VASP promotes invasiveness and metastasis of hepatocellular carcinoma.
Liu Z et al.·Theranostics
2018
Novel molecular subtypes of intracranial germ cell tumors expand therapeutic opportunities.
Li B et al.·Neuro Oncol
2024
CRKL silencing inhibits melanoma growth and enhances its chemotherapy sensitivity through the PI3K/AKT and NLRP3/GSDMD pathways.
Chen J et al.·Biochem Pharmacol
2025
Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases.
Shagisultanova E et al.·Gene
2015Review
Expanding the landscape of oncogenic drivers and treatment options in acral and mucosal melanomas by targeted genomic profiling.
Turner JA et al.·Int J Cancer
2024
Crk1/2 and CrkL play critical roles in maintaining podocyte morphology and function.
Du J et al.·Exp Cell Res
2020
Clinical significance and biological roles of CRKL in human bladder carcinoma.
Han B et al.·Tumour Biol
2014
Rare single-nucleotide variants in oculo-auriculo-vertebral spectrum (OAVS).
Zamariolli M et al.·Mol Genet Genomic Med
2019
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools