HTRA1

Chr 10ADAR

HtrA serine peptidase 1

Also known as: ARMD7, CADASIL2, CARASIL, CARASIL2, HtrA, L56, ORF480, PRSS11

NCBI Gene: 5654 ENSG00000166033 UniProt: Q92743 OMIM: 602194

This serine protease regulates extracellular matrix proteins, insulin-like growth factor availability, and TGF-beta signaling pathways. Mutations cause cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL-like syndrome), which can follow either autosomal dominant or autosomal recessive inheritance patterns. The gene shows low constraint against loss-of-function variants, consistent with both recessive disease and the observation that some individuals may tolerate heterozygous mutations.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the trypsin family of serine proteases. This protein is a secreted enzyme that is proposed to regulate the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. It has also been suggested to be a regulator of cell growth. Variations in the promoter region of this gene are the cause of susceptibility to age-related macular degeneration type 7. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.752 OMIM phenotypes

Clinical Summary— HTRA1

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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

43 unique Pathogenic / Likely Pathogenic· 185 VUS of 382 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HTRA1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.75LOEUF

pLI 0.000

Z-score 2.41

OE 0.43 (0.26–0.75)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.05Z-score

OE missense 0.81 (0.72–0.91)

195 obs / 241.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.26–0.75)

0≤0.351.4

Missense OE?0.81 (0.72–0.91)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 9 / 20.9Missense obs/exp: 195 / 241.1Syn Z: -0.51

This gene — mechanism propensity

0.7326th %ile

GOF

0.6443th %ile

LOF

0.3452th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 51% of P/LP variants are LoF

DNprediction above median

GOFprediction 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.

Literature Evidence

LOFAltogether, our findings strongly suggest that heterozygous HTRA1 stop codons are pathogenic through a haploinsufficiency mechanism.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 34270682 ↗

ClinVar Variant Classifications

382 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16

Likely Pathogenic27

VUS185

Likely Benign95

Benign25

Conflicting23

Pathogenic

Likely Pathogenic

185

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	6	2	0	16
Likely Pathogenic	14	13	0	0	27
VUS	5	163	14	3	185
Likely Benign	0	4	19	72	95
Benign	0	1	22	2	25
Conflicting	—				23
Total	27	187	57	77	371

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

View in ClinVar →

49 pathogenic / likely-pathogenic (of 55) ClinVar copy-number / structural variants overlap HTRA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →