HTRA4

Chr 8

HtrA serine peptidase 4

NCBI Gene: 203100 ENSG00000169495 UniProt: P83105 OMIM: 610700

This gene encodes a member of the HtrA family of proteases. The encoded protein contains a putative signal peptide, an insulin growth factor binding domain, a Kazal protease inhibitor domain, a conserved trypsin domain and a PDZ domain. Based on studies on other related family members, this enzyme may function as a secreted oligomeric chaperone protease to degrade misfolded secretory proteins. Other human HtrA proteins have been implicated in arthritis, tumor suppression, unfolded stress response, apoptosis, and aging. [provided by RefSeq, Oct 2008]

OMIM Research

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.34

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.34LOEUF

pLI 0.000

Z-score 0.37

OE 0.91 (0.64–1.34)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.97Z-score

OE missense 0.83 (0.74–0.93)

206 obs / 249.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.91 (0.64–1.34)

0≤0.351.4

Missense OE?0.83 (0.74–0.93)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 19 / 20.8Missense obs/exp: 206 / 249.0Syn Z: 1.10

Background carrier burden — how many people carry a rare variant somewhere in HTRA4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 77

649 rare PASS variants

Rare truncating (LoF)

1 in 880

109 rare PASS variants

Rare synonymous (reference)

1 in 150

281 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HTRA4. 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 110	1 in 1,100
South Asian	~43k	1 in 59	1 in 820
Remaining (unassigned)	~30k	1 in 60	1 in 630
European (Finnish)	~27k	1 in 310	1 in 2,200
Admixed American	~22k	1 in 74	1 in 490
African / African American	~21k	1 in 110	1 in 510
East Asian	~20k	1 in 95	1 in 690
Ashkenazi Jewish	~13k	1 in 320	≈ 1 in 5,500
Middle Eastern	~2,884	1 in 58	1 in 520

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: 8 of 9 (exon 6 below).? see exons ↓