CLSPN

Chr 1

claspin

NCBI Gene: 63967 ENSG00000092853 UniProt: Q9HAW4 OMIM: 605434

The CLSPN protein serves as an essential regulator of DNA replication checkpoint pathways, facilitating cell cycle arrest in response to DNA damage and maintaining normal replication fork progression during DNA synthesis. Mutations cause autosomal recessive developmental delay, microcephaly, and growth retardation with onset in early childhood. CLSPN is highly constrained against loss-of-function variants (LOEUF 0.40), reflecting its critical role in DNA replication and genome stability.

OMIM ResearchSummary from RefSeq, UniProt

The product of this gene is an essential upstream regulator of checkpoint kinase 1 and triggers a checkpoint arrest of the cell cycle in response to replicative stress or DNA damage. The protein is also required for efficient DNA replication during a normal S phase. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.40

Clinical Summary— CLSPN

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.

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ClinVar Variants

170 VUS of 198 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.40LOEUF

pLI 0.003

Z-score 5.61

OE 0.27 (0.19–0.40)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.85Z-score

OE missense 0.91 (0.85–0.97)

616 obs / 678.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.27 (0.19–0.40)

0≤0.351.4

Missense OE?0.91 (0.85–0.97)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 19 / 69.4Missense obs/exp: 616 / 678.6Syn Z: -0.09

This gene — mechanism propensity

0.6355th %ile

GOF

0.2696th %ile

LOF

0.4430th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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

198 submitted variants in ClinVar

ClinVar

Classification Summary

VUS170

Likely Benign8

Benign1

170

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	170	0	170
Likely Benign	6	2	8
Benign	0	1	1
Total	176	3	179

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap CLSPN — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →