HTRA2 p.Ala130=
c.390C>A · rs746431438 · VCV1027061
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 5 submitters
gnomAD v4.1
Rare
rare (popmax 0.33%, mid)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -5.1 | GERP -3.7 |
| Overall | ||
| CADD | 4.376 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.33%
Middle Eastern · 20/6,060 alleles
Filtering AF
0.219%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.183%
Overall
0.0146%
232/1,593,790 alleles · rare
exomes 203/1,441,620 · genomes 29/152,170 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.33% | 303 |
| Admixed American | 0.0584% | 1,712 |
| Remaining individualsnot grpmax-eligible | 0.034% | 2,942 |
| European (non-Finnish) | 0.0131% | 7,619 |
| African / African-American | 0.00268% | 37,274 |
| South Asian | 0.00111% | 89,872 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- HTRA2
- Protein
- p.Ala130=
- Coding
- c.390C>A
- MANE Select
- NM_013247
- dbSNP
- rs746431438
- Type
- single nucleotide variant
- Location
- chr2:74530396 (GRCh38)
- Gene constraint
- LOEUF 0.778 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 74.83 · 13 PDB
Similar variants
- HTRA2 p.Arg380Ter Pathogenic ★★ same type
- HTRA2 p.Gln82Ter Pathogenic ★★ same type
- AUP1 p.Pro9Ser Uncertain significance ★★ ⚠ same type
- HTRA2 c.507-10T>A Uncertain significance ★★ same type
- HTRA2 c.507-9C>A Uncertain significance ★★ same type
- HTRA2 p.Ala110Gly Uncertain significance ★★ ⚠ same type
- HTRA2 p.Ala415Thr Uncertain significance ★★ ⚠ same type
- HTRA2 p.Arg252Gln Uncertain significance ★★ ⚠ same type
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/htra2-p-ala130 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown