Is HTRA1 p.Phe286Ser (c.857T>C) pathogenic?

HTRA1 p.Phe286Ser (c.857T>C) is classified Uncertain significance in HTRA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-23). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1; Associated with cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2.

How common is HTRA1 p.Phe286Ser (c.857T>C) in the general population?

HTRA1 p.Phe286Ser (c.857T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HTRA1 p.Phe286Ser (c.857T>C)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

HTRA1 p.Phe286Ser

Q: What condition is associated with HTRA1 p.Phe286Ser (c.857T>C)?

HTRA1 p.Phe286Ser (c.857T>C) is associated with cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 (ClinVar).

c.857T>C · rs2497648414 · VCV1709222

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic · top 5% in HTRA1
REVEL	0.938	strongly pathogenic-leaning
SaProt	LLR -13.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.5, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 47 kb · p 6.7e-12 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HTRA1
Protein: p.Phe286Ser
Coding: c.857T>C
MANE Select: NM_002775
dbSNP: rs2497648414
Type: single nucleotide variant
Location: chr10:122506770 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.30 · 18 PDB
Residue 286: a UniProt-annotated variant site (in cadasil2; loss of proteolytic activity); the 'serine protease' region; a β-strand

Full HTRA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HTRA1 p.Arg166Cys Pathogenic/Likely pathogenic ★★ same condition
HTRA1 p.Arg166His Pathogenic/Likely pathogenic ★★ same condition
HTRA1 p.Arg166Leu Pathogenic ★★ same condition
HTRA1 p.Arg302Gln Pathogenic/Likely pathogenic ★★ same condition
HTRA1 p.Arg302Ter Pathogenic/Likely pathogenic ★★ same condition
HTRA1 p.Gln289Ter Pathogenic ★★ same condition
HTRA1 p.Gly283Arg Pathogenic/Likely pathogenic ★★ same condition
HTRA1 p.Arg197Gln Uncertain significance ★★ ⚠ same condition

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/htra1-p-phe286ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown