CENPS

Chr 1

centromere protein S

Also known as: APITD1, CENP-S, FAAP16, MHF1

NCBI Gene: 378708 ENSG00000175279 UniProt: Q8N2Z9 OMIM: 609130

The protein is a DNA-binding component of the Fanconi anemia core complex required for DNA damage response and also functions as part of the kinetochore complex essential for proper chromosome segregation during cell division. Mutations cause Fanconi anemia, an autosomal recessive disorder characterized by bone marrow failure, developmental abnormalities, and increased cancer predisposition. The gene shows low constraint against loss-of-function variants, consistent with the recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

This gene was identified in the neuroblastoma tumor suppressor candidate region on chromosome 1p36. It contains a TFIID-31 domain, similar to that found in TATA box-binding protein-associated factor, TAF(II)31, which is required for p53-mediated transcription activation. This gene was expressed at very low levels in neuroblastoma tumors, and was shown to reduce cell growth in neuroblastoma cells, suggesting that it may have a role in a cell death pathway. The protein is a component of multiple complexes, including the Fanconi anemia (FA) core complex, the APITD1/CENPS complex, and the CENPA-CAD (nucleosome distal) complex. Known functions include an involvement with chromatin associations of the FA core complex, and a role in the stable assembly of the outer kinetochore. Alternative splicing of this gene results in multiple transcript variants. Naturally occurring read-through transcripts also exist between this gene and the downstream cortistatin (CORT) gene, as represented in GeneID:100526739. An APITD1-related pseudogene has been identified on chromosome 7. [provided by RefSeq, Nov 2010]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.71

Clinical Summary— CENPS

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

12 VUS of 14 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?

1.71LOEUF

pLI 0.000

Z-score 0.02

OE 0.99 (0.58–1.71)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.11Z-score

OE missense 1.33 (1.15–1.56)

116 obs / 86.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.99 (0.58–1.71)

0≤0.351.4

Missense OE?1.33 (1.15–1.56)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 8 / 8.1Missense obs/exp: 116 / 86.9Syn Z: 0.51

This gene — mechanism propensity

0.6260th %ile

GOF

0.4381th %ile

LOF

0.3649th %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

14 submitted variants in ClinVar

ClinVar

Classification Summary

VUS12

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	12	12
Likely Benign	0	0
Benign	0	0
Total	12	12

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

View in ClinVar →

35 pathogenic / likely-pathogenic (of 47) ClinVar copy-number / structural variants overlap CENPS — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →