HTRA3

Chr 4

HtrA serine peptidase 3

Also known as: Prsp, Tasp

NCBI Gene: 94031 ENSG00000170801 UniProt: P83110 OMIM: 608785

The protein is a serine protease that cleaves extracellular matrix components including decorin, biglycan, and fibronectin, and may inhibit TGF-beta signaling. Biallelic mutations cause autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), characterized by progressive subcortical vascular dementia, alopecia, and skeletal abnormalities typically beginning in adulthood. The gene shows tolerance to loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, UniProt

Enables endopeptidase activity; identical protein binding activity; and serine-type peptidase activity. Involved in proteolysis. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Active trials

—

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.23

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.23LOEUF

pLI 0.000

Z-score 0.85

OE 0.78 (0.50–1.23)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.50Z-score

OE missense 0.91 (0.82–1.02)

243 obs / 265.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.78 (0.50–1.23)

0≤0.351.4

Missense OE?0.91 (0.82–1.02)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 13 / 16.8Missense obs/exp: 243 / 265.8Syn Z: -0.18

Background carrier burden — how many people carry a rare variant somewhere in HTRA3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 100

683 rare PASS variants

Rare truncating (LoF)

1 in 2,000

89 rare PASS variants

Rare synonymous (reference)

1 in 98

325 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HTRA3. 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)	~556k	1 in 120	1 in 2,100
South Asian	~43k	1 in 62	1 in 1,500
Remaining (unassigned)	~30k	1 in 95	1 in 2,100
European (Finnish)	~27k	1 in 420	≈ 1 in 8,800
Admixed American	~22k	1 in 77	1 in 1,700
African / African American	~21k	1 in 59	1 in 1,000
East Asian	~20k	1 in 110	1 in 1,200
Ashkenazi Jewish	~13k	1 in 260	none seen
Middle Eastern	~2,884	1 in 100	≈ 1 in 930

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): 8 of 9 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 9.? see exons ↓