MBTPS2

Chr XXLR

membrane bound transcription factor peptidase, site 2

Also known as: BRESEK, IFAP, KFSD, KFSDX, OI19, OLMSX, S2P

NCBI Gene: 51360 ENSG00000012174 UniProt: O43462 OMIM: 300294

This intramembrane zinc metalloprotease cleaves sterol regulatory element-binding proteins (SREBPs) and ATF6 to activate transcription factors essential for cholesterol homeostasis and ER stress response. X-linked recessive mutations cause IFAP syndrome (ichthyosis follicularis with atrichia and photophobia), keratosis follicularis spinulosa decalvans, osteogenesis imperfecta type XIX, and possibly Olmsted syndrome through loss of function. The pathogenic mechanism involves impaired cholesterol homeostasis and defective ER stress response due to reduced protease activity.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a intramembrane zinc metalloprotease, which is essential in development. This protease functions in the signal protein activation involved in sterol control of transcription and the ER stress response. Mutations in this gene have been associated with ichthyosis follicularis with atrichia and photophobia (IFAP syndrome); IFAP syndrome has been quantitatively linked to a reduction in cholesterol homeostasis and ER stress response.[provided by RefSeq, Aug 2009]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Olmsted syndrome, X-linkedMIM #300918

XLR

IFAP syndrome with or without BRESHECK syndromeMIM #308205

XLR

Keratosis follicularis spinulosa decalvans, X-linkedMIM #308800

XLR

Osteogenesis imperfecta, type XIXMIM #301014

XLR

UniProtIFAP syndrome 1, with or without Bresheck syndrome

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · IFAP syndrome 1, with or without BRESHECK syndrome · XL · ClinGen 2021

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.17

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

LoF Constraint?

0.17LOEUF

pLI 0.998

Z-score 3.89

OE 0.00 (0.00–0.17)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.09Z-score

OE missense 0.58 (0.49–0.68)

112 obs / 194.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.17)

0≤0.351.4

Missense OE?0.58 (0.49–0.68)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 0 / 17.6Missense obs/exp: 112 / 194.0Syn Z: 0.14

Background carrier burden — how many people carry a rare variant somewhere in MBTPS2?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 200

267 rare PASS variants

Rare truncating (LoF)

1 in 79,000

4 rare PASS variants

Rare synonymous (reference)

1 in 270

146 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MBTPS2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 220	1 in 77,000
South Asian	~36k	1 in 170	≈ 1 in 34,000
Remaining (unassigned)	~31k	1 in 180	none seen
European (Finnish)	~27k	1 in 1,200	none seen
Admixed American	~23k	1 in 180	≈ 1 in 22,000
African / African American	~21k	1 in 210	none seen
East Asian	~20k	1 in 300	none seen
Ashkenazi Jewish	~13k	1 in 860	none seen
Middle Eastern	~2,758	1 in 250	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 11 coding exons well covered in gnomAD exomes and genomes.? see exons ↓