Is HTRA2 p.Cys71= (c.213C>T) pathogenic?

HTRA2 p.Cys71= (c.213C>T) is classified Likely benign in HTRA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-21). Very rare (popmax 0.000594%, nfe).

How common is HTRA2 p.Cys71= (c.213C>T) in the general population?

HTRA2 p.Cys71= (c.213C>T) is very rare (popmax 0.000594%, nfe) (gnomAD).

HTRA2 p.Cys71=

c.213C>T · rs2529878193 · VCV2025809

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000594%, nfe)

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 0.13	GERP -0.4, phastCons 0.072
Overall
CADD	5.001	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000594% European (non-Finnish) · 7/1,178,642 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000435% 7/1,610,610 alleles · very rare exomes 7/1,458,254 · genomes 0/152,356 · joint denominator

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.Cys71=
Coding: c.213C>T
MANE Select: NM_013247
dbSNP: rs2529878193
Type: single nucleotide variant
Location: chr2:74530219 (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

Similar variants

HTRA2 p.Cys71Tyr Uncertain significance ★ ⚠ 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
HTRA2 p.Ala415Thr 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-cys71 (accessed [today's date]).

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