Is HTRA2 p.Arg209= (c.627A>G) pathogenic?

HTRA2 p.Arg209= (c.627A>G) is classified Likely benign in HTRA2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). Rare (popmax 0.214%, mid); Associated with Parkinson disease 13, autosomal dominant, susceptibility to.

What condition is associated with HTRA2 p.Arg209= (c.627A>G)?

HTRA2 p.Arg209= (c.627A>G) is associated with Parkinson disease 13, autosomal dominant, susceptibility to (ClinVar).

How common is HTRA2 p.Arg209= (c.627A>G) in the general population?

HTRA2 p.Arg209= (c.627A>G) is rare (popmax 0.214%, mid) (gnomAD).

HTRA2 p.Arg209=

c.627A>G · rs149169879 · VCV337132

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.214%, mid)

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 · A>T here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.5	GERP -1.7, phastCons 1
Overall
CADD	12.77	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.214% Middle Eastern · 13/6,062 alleles

Filtering AF 0.127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.0498% 804/1,614,136 alleles · rare exomes 687/1,461,890 · genomes 117/152,246 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.787%	127
Middle Easterngrpmax	0.214%	466
Admixed American	0.117%	857
Remaining individualsnot grpmax-eligible	0.104%	962
African / African-American	0.0387%	2,587
European (non-Finnish)	0.033%	3,033
South Asian	0.00439%	22,770
Finnishnot grpmax-eligible	0.00156%	64,022

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg209=
Coding: c.627A>G
MANE Select: NM_013247
dbSNP: rs149169879
Type: single nucleotide variant
Location: chr2:74530737 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.83 · 13 PDB
Residue 209: a β-strand; the 'serine protease' region

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

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
HTRA2 c.*94C>T 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-arg209 (accessed [today's date]).

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