Is BRF1 p.Ala232Pro (c.694G>C) pathogenic?

BRF1 p.Ala232Pro (c.694G>C) is classified Uncertain significance in BRF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-09). AlphaMissense: likely pathogenic (0.9983); Very rare (popmax 0.00017%, nfe).

How common is BRF1 p.Ala232Pro (c.694G>C) in the general population?

BRF1 p.Ala232Pro (c.694G>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about BRF1 p.Ala232Pro (c.694G>C)?

AlphaMissense predicts likely pathogenic (score 0.9983) — an in-silico prediction, not a clinical call.

BRF1 p.Ala232Pro

c.694G>C · VCV4882984

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9983 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9983	likely pathogenic
REVEL	0.893	moderately pathogenic-leaning
SaProt	LLR -15.02	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.91	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.70	loss · gain 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00017% European (non-Finnish) · 2/1,179,710 alleles

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

Overall 0.000124% 2/1,611,278 alleles · very rare exomes 2/1,458,930 · genomes 0/152,348 · 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: BRF1
Protein: p.Ala232Pro
Coding: c.694G>C
MANE Select: NM_001519
Type: single nucleotide variant
Location: chr14:105241265 (GRCh38)
Structure: AlphaFold pLDDT 59.70 · 2 PDB
Residue 232: the 'necessary for mrna decay activation' region

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

Similar variants

BRF1 p.Ala232= Conflicting classifications of pathogenicity ★ same residue
BRF1 p.Pro292His Pathogenic/Likely pathogenic ★★ same type
BRF1 p.Ser226Leu Pathogenic/Likely pathogenic ★★ same type
BRF1 p.Ala565Ser Uncertain significance ★★ ⚠ same type
BRF1 p.Arg213Lys Uncertain significance ★★ ⚠ same type
BRF1 p.Arg216Gln Uncertain significance ★★ ⚠ same type
BRF1 p.Arg261Gln Uncertain significance ★★ ⚠ same type
BRF1 p.Arg302Trp 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/brf1-p-ala232pro (accessed [today's date]).

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