Is BRF1 p.Pro292His (c.875C>A) pathogenic?

BRF1 p.Pro292His (c.875C>A) is classified Pathogenic/Likely pathogenic in BRF1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-02-23). AlphaMissense: likely pathogenic (0.999); Very rare (popmax 0.00333%, amr); Associated with cerebellar-facial-dental syndrome.

What condition is associated with BRF1 p.Pro292His (c.875C>A)?

BRF1 p.Pro292His (c.875C>A) is associated with cerebellar-facial-dental syndrome (ClinVar).

How common is BRF1 p.Pro292His (c.875C>A) in the general population?

BRF1 p.Pro292His (c.875C>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about BRF1 p.Pro292His (c.875C>A)?

AlphaMissense predicts likely pathogenic (score 0.999) — an in-silico prediction, not a clinical call.

BRF1 p.Pro292His

c.875C>A · rs606231450 · VCV161426

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.999 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebellar-facial-dental syndrome

Computational evidence

Protein change
AlphaMissense	0.999	likely pathogenic ✓ concordant with ClinVar
REVEL	0.775	moderately pathogenic-leaning
SaProt	LLR -16.48	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Overall
CADD	25.9	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 0.00333% Admixed American · 2/60,004 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000248% 4/1,613,402 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,002
European (non-Finnish)	0.000169%	590,016

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: BRF1
Protein: p.Pro292His
Coding: c.875C>A
MANE Select: NM_004926 · reported on NM_001519
dbSNP: rs606231450
Type: single nucleotide variant
Location: chr14:105226674 (GRCh38)
Structure: AlphaFold pLDDT 59.70 · 2 PDB
Residue 292: the 'necessary for mrna decay activation' region; the 'disordered' region

Full BRF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cerebellar-facial-dental syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BRF1 p.Pro292Arg Likely pathogenic ★ same residue
BRF1 p.Pro292Leu Uncertain significance ★ ⚠ same residue
BRF1 p.Pro292= Likely benign ★ same residue
BRF1 p.Ser226Leu Pathogenic/Likely pathogenic ★★ same condition
BRF1 p.Ala565Ser Uncertain significance ★★ ⚠ same condition
BRF1 p.Gly402Ser Uncertain significance ★★ ⚠ same condition
BRF1 p.Pro183= Benign/Likely benign ★★ same condition
BRF1 c.1378-12G>C Uncertain significance ★ 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/brf1-p-pro292his (accessed [today's date]).

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