Is HTRA1 p.Pro4Ser (c.10C>T) pathogenic?

HTRA1 p.Pro4Ser (c.10C>T) is classified Uncertain significance in HTRA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-24). AlphaMissense: likely benign (0.0712); Very rare (popmax 0.00777%, nfe); Associated with macular degeneration.

What condition is associated with HTRA1 p.Pro4Ser (c.10C>T)?

HTRA1 p.Pro4Ser (c.10C>T) is associated with macular degeneration (ClinVar).

How common is HTRA1 p.Pro4Ser (c.10C>T) in the general population?

HTRA1 p.Pro4Ser (c.10C>T) is very rare (popmax 0.00777%, nfe) (gnomAD).

What do computational predictors say about HTRA1 p.Pro4Ser (c.10C>T)?

AlphaMissense predicts likely benign (score 0.0712) — an in-silico prediction, not a clinical call.

HTRA1 p.Pro4Ser

c.10C>T · rs1325725955 · VCV877205

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0712 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00777%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

macular degeneration

Computational evidence

Protein change
AlphaMissense	0.0712	likely benign
REVEL	0.262	benign-leaning
SaProt	LLR -7.66	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 -0.14	GERP -3
Regional constraint	o/e 1.33	unconstrained · MANE · 189 bp · p 0.0029 · regional, not allelic
Overall
CADD	11.57	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 0.00777% European (non-Finnish) · 79/1,016,340 alleles

Filtering AF 0.00634% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00587%

Overall 0.00601% 79/1,313,662 alleles · very rare exomes 74/1,165,794 · genomes 5/147,868 · 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: HTRA1
Protein: p.Pro4Ser
Coding: c.10C>T
MANE Select: NM_002775
dbSNP: rs1325725955
Type: single nucleotide variant
Location: chr10:122461662 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.30 · 18 PDB

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

Disease context

macular degeneration — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HTRA1 p.Pro4= Conflicting classifications of pathogenicity ★ same residue
HTRA1 p.Ala445Thr Uncertain significance ★★ ⚠ same condition
HTRA1 p.Asp420Glu Uncertain significance ★★ ⚠ same condition
HTRA1 p.Gln151Lys Uncertain significance ★★ ⚠ same condition
HTRA1 p.Ile282Leu Uncertain significance ★★ same condition
HTRA1 p.Pro193Leu Uncertain significance ★★ ⚠ same condition
HTRA1 c.1274+14G>A Benign ★★ same condition
HTRA1 c.1274+8G>A Benign/Likely benign ★★ 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/htra1-p-pro4ser (accessed [today's date]).

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