Is BROX p.Pro9Ala (c.25C>G) pathogenic?

BROX p.Pro9Ala (c.25C>G) is classified Uncertain significance in BROX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: likely benign (0.183); Absent from gnomAD v4.1.

How common is BROX p.Pro9Ala (c.25C>G) in the general population?

BROX p.Pro9Ala (c.25C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BROX p.Pro9Ala (c.25C>G)?

AlphaMissense predicts likely benign (score 0.183) — an in-silico prediction, not a clinical call.

BROX p.Pro9Ala

c.25C>G · VCV4216319

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.183 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.183	likely benign
REVEL	0.855	moderately pathogenic-leaning
SaProt	LLR -6.51	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 17 kb · p 0.43 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BROX
Protein: p.Pro9Ala
Coding: c.25C>G
MANE Select: NM_144695
Type: single nucleotide variant
Location: chr1:222715724 (GRCh38)
Gene constraint: LOEUF 1.123 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.15 · 7 PDB
Residue 9: an α-helix

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

Similar variants

BROX p.Ala169Val Uncertain significance ★ ⚠ same type
BROX p.Ala191Val Uncertain significance ★ ⚠ same type
BROX p.Ala213Val Uncertain significance ★ ⚠ same type
BROX p.Arg178Gln Uncertain significance ★ ⚠ same type
BROX p.Arg378Lys Uncertain significance ★ ⚠ same type
BROX p.Asn117Ser Uncertain significance ★ ⚠ same type
BROX p.Asn19Ser Uncertain significance ★ ⚠ same type
BROX p.Asn218Ser 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/brox-p-pro9ala (accessed [today's date]).

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