Is HTRA2 p.Arg15Pro (c.44G>C) pathogenic?

HTRA2 p.Arg15Pro (c.44G>C) is classified Uncertain significance in HTRA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-01). AlphaMissense: likely benign (0.083); Very rare (popmax 0.00135%, afr).

How common is HTRA2 p.Arg15Pro (c.44G>C) in the general population?

HTRA2 p.Arg15Pro (c.44G>C) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about HTRA2 p.Arg15Pro (c.44G>C)?

AlphaMissense predicts likely benign (score 0.083) — an in-silico prediction, not a clinical call.

HTRA2 p.Arg15Pro

c.44G>C · rs1275995075 · VCV2014283

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.083 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.083	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -8.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.1	GERP -3.4, phastCons 0.007
Regional constraint	o/e 1.08	unconstrained · MANE · 442 bp · p 0.24 · regional, not allelic
Overall
CADD	15.25	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 0.00135% African / African-American · 1/74,284 alleles

Overall 6.33e-05% 1/1,580,150 alleles · very rare exomes 0/1,427,962 · genomes 1/152,188 · 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.Arg15Pro
Coding: c.44G>C
MANE Select: NM_013247
dbSNP: rs1275995075
Type: single nucleotide variant
Location: chr2:74530050 (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.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
HTRA2 p.Arg252Gln 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-arg15pro (accessed [today's date]).

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