Is HTRA2 p.Pro33Ser (c.97C>T) pathogenic?

HTRA2 p.Pro33Ser (c.97C>T) is classified Uncertain significance in HTRA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-04). AlphaMissense: likely benign (0.0883); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with HTRA2 p.Pro33Ser (c.97C>T)?

HTRA2 p.Pro33Ser (c.97C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HTRA2 p.Pro33Ser (c.97C>T) in the general population?

HTRA2 p.Pro33Ser (c.97C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about HTRA2 p.Pro33Ser (c.97C>T)?

AlphaMissense predicts likely benign (score 0.0883) — an in-silico prediction, not a clinical call.

HTRA2 p.Pro33Ser

c.97C>T · VCV3285066

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0883 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0883	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -5.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.6, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 442 bp · p 0.24 · regional, not allelic
Overall
CADD	19.03	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,878 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000275% 4/1,454,378 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,878
European (non-Finnish)	0.000255%	391,653

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.Pro33Ser
Coding: c.97C>T
MANE Select: NM_013247
Type: single nucleotide variant
Location: chr2:74530103 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HTRA2 p.Ala110Gly Uncertain significance ★★ ⚠ same condition
HTRA2 p.Ala415Thr Uncertain significance ★★ ⚠ same condition
HTRA2 p.Arg360Cys Uncertain significance ★★ ⚠ same condition
HTRA2 p.Arg36Trp Uncertain significance ★★ ⚠ same condition
HTRA2 p.Arg404Trp Uncertain significance ★★ ⚠ same condition
HTRA2 p.Arg60Trp Uncertain significance ★★ ⚠ same condition
HTRA2 p.Arg80Leu Uncertain significance ★★ ⚠ same condition
HTRA2 p.Glu429Lys 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-pro33ser (accessed [today's date]).

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