Is HTRA2 p.Val206= (c.618C>G) pathogenic?

HTRA2 p.Val206= (c.618C>G) is classified Likely benign in HTRA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-05-01). Ultra-rare (popmax 0.033%, mid); Associated with Parkinson disease 13, autosomal dominant, susceptibility to.

How common is HTRA2 p.Val206= (c.618C>G) in the general population?

HTRA2 p.Val206= (c.618C>G) is ultra-rare (popmax 0.033%, mid) (gnomAD).

HTRA2 p.Val206=

Q: What condition is associated with HTRA2 p.Val206= (c.618C>G)?

HTRA2 p.Val206= (c.618C>G) is associated with Parkinson disease 13, autosomal dominant, susceptibility to, 3-methylglutaconic aciduria type 8 (ClinVar).

c.618C>G · rs186272815 · VCV1188327

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.1	GERP -3.4, phastCons 0.42
Overall
CADD	8.172	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00304% 49/1,614,202 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0112%	8,930
South Asian	0.00329%	30,361
European (non-Finnish)	0.00305%	32,779
African / African-American	0.00133%	75,052

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.Val206=
Coding: c.618C>G
MANE Select: NM_013247
dbSNP: rs186272815
Type: single nucleotide variant
Location: chr2:74530728 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.83 · 13 PDB
Residue 206: 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

Also linked: 3-methylglutaconic aciduria type 8

Similar variants

HTRA2 p.Arg380Ter Pathogenic ★★ same condition
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.Arg252Gln Uncertain significance ★★ ⚠ same condition
HTRA2 p.Arg432Ter Uncertain significance ★★ same condition
HTRA2 p.Arg49Pro Uncertain significance ★★ ⚠ same condition
HTRA2 p.Gly26Glu 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/htra2-p-val206 (accessed [today's date]).

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