Is HTRA2 p.Ala141= (c.423T>C) pathogenic?

HTRA2 p.Ala141= (c.423T>C) is classified Likely benign in HTRA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-19). Absent from gnomAD v4.1.

How common is HTRA2 p.Ala141= (c.423T>C) in the general population?

HTRA2 p.Ala141= (c.423T>C) is absent from gnomAD v4.1 (gnomAD).

HTRA2 p.Ala141=

c.423T>C · rs2529880681 · VCV3004313

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 0.12	GERP 0.66, phastCons 0.031
Overall
CADD	11.22	PHRED · no single calibrated threshold — expert panels disagree

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: HTRA2
Protein: p.Ala141=
Coding: c.423T>C
MANE Select: NM_013247
dbSNP: rs2529880681
Type: single nucleotide variant
Location: chr2:74530429 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.83 · 13 PDB
Residue 141: a UniProt-annotated variant site (may be a risk factor for parkinson disease; reduced protease activity)

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

Similar variants

HTRA2 p.Ala141Ser Benign ★★ same residue
HTRA2 p.Ala141fs Pathogenic ★ same residue
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

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-ala141 (accessed [today's date]).

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