Is HTRA1 p.Pro4= (c.12G>T) pathogenic?

HTRA1 p.Pro4= (c.12G>T) is classified Conflicting classifications of pathogenicity in HTRA1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-10). Ultra-rare (popmax 0.0297%, mid); Associated with macular degeneration.

What condition is associated with HTRA1 p.Pro4= (c.12G>T)?

HTRA1 p.Pro4= (c.12G>T) is associated with macular degeneration (ClinVar).

How common is HTRA1 p.Pro4= (c.12G>T) in the general population?

HTRA1 p.Pro4= (c.12G>T) is ultra-rare (popmax 0.0297%, mid) (gnomAD).

HTRA1 p.Pro4=

c.12G>T · rs761008513 · VCV877206

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0297%, mid)

Conditions

macular degeneration

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 1.9	GERP -2.9, phastCons 0.78
Overall
CADD	9.675	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0297% Middle Eastern · 1/3,370 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0249%

Overall 0.0236% 310/1,312,120 alleles · ultra-rare exomes 280/1,164,434 · genomes 30/147,686 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0297%	3,370
European (non-Finnish)	0.0287%	3,489
Finnishnot grpmax-eligible	0.0224%	4,463
Remaining individualsnot grpmax-eligible	0.0131%	7,641
African / African-American	0.00635%	15,759
Admixed American	0.00272%	36,818

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.Pro4=
Coding: c.12G>T
MANE Select: NM_002775
dbSNP: rs761008513
Type: single nucleotide variant
Location: chr10:122461664 (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.Pro4Ser Uncertain significance ★★ ⚠ 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-pro4 (accessed [today's date]).

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