MBTPS1

Chr 16AR

membrane bound transcription factor peptidase, site 1

Also known as: CAOP, PCSK8, S1P, SEDKF, SKI-1

NCBI Gene: 8720 ENSG00000140943 UniProt: Q14703 OMIM: 603355

The protein encoded by this gene is a serine protease that cleaves multiple substrates including sterol regulatory element-binding proteins (SREBPs), ATF6, and other proteins involved in cholesterol metabolism, ER stress response, lysosomal enzyme trafficking, and collagen processing. Mutations cause CAOP syndrome and Kondo-Fu type spondyloepiphyseal dysplasia, both inherited in an autosomal recessive pattern. The gene is highly constrained against loss-of-function variants (LOEUF 0.588), and the associated conditions primarily affect skeletal development and growth.

GeneReviews OMIM ResearchSummary from OMIM, UniProt

This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER and sorts to the cis/medial-Golgi where a second autocatalytic event takes place and the catalytic activity is acquired. It encodes a type 1 membrane bound protease which is ubiquitously expressed and regulates cholesterol or lipid homeostasis via cleavage of substrates at non-basic residues. Mutations in this gene may be associated with lysosomal dysfunction. [provided by RefSeq, Feb 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.592 OMIM phenotypes

Clinical Summary— MBTPS1

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Gene-Disease Validity (ClinGen)

spondyloepiphyseal dysplasia, kondo-fu type · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

31 unique Pathogenic / Likely Pathogenic· 267 VUS of 616 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MBTPS1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.59LOEUF

pLI 0.000

Z-score 4.08

OE 0.42 (0.30–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-1.45Z-score

OE missense 1.16 (1.09–1.24)

715 obs / 613.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.42 (0.30–0.59)

0≤0.351.4

Missense OE?1.16 (1.09–1.24)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 24 / 57.4Missense obs/exp: 715 / 613.8Syn Z: -2.42

This gene — mechanism propensity

0.6453th %ile

GOF

0.4678th %ile

LOF

0.4136th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-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

LOF65% of P/LP variants are LoF

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

616 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23

Likely Pathogenic8

VUS267

Likely Benign236

Benign35

Conflicting7

Pathogenic

Likely Pathogenic

267

VUS

236

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	15	2	6	0	23
Likely Pathogenic	5	3	0	0	8
VUS	0	256	9	2	267
Likely Benign	0	11	102	123	236
Benign	0	2	21	12	35
Conflicting	—				7
Total	20	274	138	137	576

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

View in ClinVar →

45 pathogenic / likely-pathogenic (of 80) ClinVar copy-number / structural variants overlap MBTPS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →