Is HTRA1 p.Pro43Ser (c.127C>T) pathogenic?

HTRA1 p.Pro43Ser (c.127C>T) is classified Uncertain significance in HTRA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-02). AlphaMissense: likely benign (0.1204); Very rare (popmax 0.00535%, amr).

How common is HTRA1 p.Pro43Ser (c.127C>T) in the general population?

HTRA1 p.Pro43Ser (c.127C>T) is very rare (popmax 0.00535%, amr) (gnomAD).

What do computational predictors say about HTRA1 p.Pro43Ser (c.127C>T)?

AlphaMissense predicts likely benign (score 0.1204) — an in-silico prediction, not a clinical call.

HTRA1 p.Pro43Ser

c.127C>T · rs1435531631 · VCV1517131

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1204 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00535%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1204	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -8.58	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 0.42	GERP -1.5
Regional constraint	o/e 1.33	unconstrained · MANE · 189 bp · p 0.0029 · regional, not allelic
Overall
CADD	15.39	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 0.00535% Admixed American · 1/18,676 alleles

Filtering AF 9.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000381% 4/1,050,816 alleles · very rare exomes 2/903,298 · genomes 2/147,518 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00535%	18,676
European (non-Finnish)	0.000343%	291,318

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: HTRA1
Protein: p.Pro43Ser
Coding: c.127C>T
MANE Select: NM_002775
dbSNP: rs1435531631
Type: single nucleotide variant
Location: chr10:122461779 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.30 · 18 PDB
Residue 43: the igfbp n-terminal domain; an α-helix

Full HTRA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HTRA1 c.972+1G>A Pathogenic/Likely pathogenic ★★ same type
HTRA1 p.Arg166Cys Pathogenic/Likely pathogenic ★★ same type
HTRA1 p.Arg166His Pathogenic/Likely pathogenic ★★ same type
HTRA1 p.Arg166Leu Pathogenic ★★ same type
HTRA1 p.Arg274Gln Pathogenic/Likely pathogenic ★★ same type
HTRA1 p.Arg302Gln Pathogenic/Likely pathogenic ★★ same type
HTRA1 p.Arg302Ter Pathogenic/Likely pathogenic ★★ same type
HTRA1 p.Arg370Ter Pathogenic/Likely pathogenic ★★ 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/htra1-p-pro43ser (accessed [today's date]).

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