Is BROX p.Phe356Val (c.1066T>G) pathogenic?

BROX p.Phe356Val (c.1066T>G) is classified Uncertain significance in BROX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-22). AlphaMissense: ambiguous (0.4295); Very rare (popmax 0.00017%, nfe).

How common is BROX p.Phe356Val (c.1066T>G) in the general population?

BROX p.Phe356Val (c.1066T>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about BROX p.Phe356Val (c.1066T>G)?

AlphaMissense predicts ambiguous (score 0.4295) — an in-silico prediction, not a clinical call.

BROX p.Phe356Val

c.1066T>G · rs1657928838 · VCV2384255

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4295 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4295	ambiguous
REVEL	0.301	indeterminate
SaProt	LLR -10.08	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 17 kb · p 0.43 · regional, not allelic
Overall
CADD	26.8	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

Grpmax group 0.00017% European (non-Finnish) · 2/1,177,186 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000138% 2/1,450,472 alleles · very rare

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: BROX
Protein: p.Phe356Val
Coding: c.1066T>G
MANE Select: NM_144695
dbSNP: rs1657928838
Type: single nucleotide variant
Location: chr1:222731433 (GRCh38)
Gene constraint: LOEUF 1.123 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.15 · 7 PDB
Residue 356: the bro1 domain

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-phe356val (accessed [today's date]).

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