CRNKL1

Chr 20AD

crooked neck pre-mRNA splicing factor 1

Also known as: CLF, CRN, Clf1, HCRN, MGCH, MSTP021, SYF3

NCBI Gene: 51340ENSG00000101343UniProt: Q9BZJ0

The crooked neck (crn) gene of Drosophila is essential for embryogenesis and is thought to be involved in cell cycle progression and pre-mRNA splicing. A protein encoded by this human locus has been found to localize to pre-mRNA splicing complexes in the nucleus and is necessary for pre-mRNA splicing. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2013]

Primary Disease Associations & Inheritance

Microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasiaMIM #621436
AD
0
Active trials
27
Pathogenic / LP
99
ClinVar variants
6
Pubs (1 yr)
0.9
Missense Z
0.55
LOEUF
Clinical Summary— CRNKL1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
27 Pathogenic / Likely Pathogenic· 67 VUS of 99 total submissions
Some data sources returned errors (1)

pubtator: TimeoutError: The operation was aborted due to timeout

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.55LOEUF
pLI 0.000
Z-score 4.16
OE 0.37 (0.26–0.55)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
0.88Z-score
OE missense 0.89 (0.82–0.96)
420 obs / 473.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.37 (0.26–0.55)
0≤0.351.4
Missense OE0.89 (0.82–0.96)
0≤0.61.4
Synonymous OE1.08
0≤1.21.6
LoF obs/exp: 19 / 51.1Missense obs/exp: 420 / 473.9Syn Z: -0.80
DNGOF
DN
0.76top 25%
GOF
0.72top 25%
LOF
0.3065th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

99 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24
Likely Pathogenic3
VUS67
Likely Benign5
24
Pathogenic
3
Likely Pathogenic
67
VUS
5
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
3
21
0
24
Likely Pathogenic
0
0
3
0
3
VUS
0
65
2
0
67
Likely Benign
0
4
1
0
5
Benign
0
0
0
0
0
Total07227099

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

View in ClinVar →

CRNKL1 · protein map & ClinVar variants

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

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

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients