Is HTRA2 p.Ser352= (c.1056C>T) pathogenic?

HTRA2 p.Ser352= (c.1056C>T) is classified Conflicting classifications of pathogenicity in HTRA2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-08). Ultra-rare (popmax 0.01%, amr); Associated with Parkinson disease 13, autosomal dominant, susceptibility to.

What condition is associated with HTRA2 p.Ser352= (c.1056C>T)?

HTRA2 p.Ser352= (c.1056C>T) is associated with Parkinson disease 13, autosomal dominant, susceptibility to (ClinVar).

How common is HTRA2 p.Ser352= (c.1056C>T) in the general population?

HTRA2 p.Ser352= (c.1056C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

HTRA2 p.Ser352=

c.1056C>T · rs781540048 · VCV895799

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Conditions

Parkinson disease 13, autosomal dominant, susceptibility to

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.52 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.9	GERP -1.6, phastCons 1
Overall
CADD	9.224	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,996 alleles

Filtering AF 0.00782% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00727%

Overall 0.00775% 125/1,613,846 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,999
European (non-Finnish)	0.00924%	10,826
South Asian	0.00659%	15,177
African / African-American	0.00267%	37,441
East Asian	0.00223%	44,892
Remaining individualsnot grpmax-eligible	0.0016%	62,468

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.Ser352=
Coding: c.1056C>T
MANE Select: NM_013247
dbSNP: rs781540048
Type: single nucleotide variant
Location: chr2:74531866 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.83 · 13 PDB

Full HTRA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Parkinson disease 13, autosomal dominant, susceptibility to — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HTRA2 p.Ser352Cys Uncertain significance ★ ⚠ same residue
AUP1 p.Pro9Ser Uncertain significance ★★ ⚠ same condition
HTRA2 c.507-10T>A Uncertain significance ★★ same condition
HTRA2 c.507-9C>A Uncertain significance ★★ same condition
HTRA2 p.Arg432Ter Uncertain significance ★★ same condition
HTRA2 p.Gly26Glu Uncertain significance ★★ ⚠ same condition
HTRA2 p.Thr449Ile Uncertain significance ★★ ⚠ same condition
HTRA2 c.1046-5C>G Likely benign ★★ 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/htra2-p-ser352 (accessed [today's date]).

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