Is BRF1 p.Ser293fs (c.876dup) pathogenic?

BRF1 p.Ser293fs (c.876dup) is classified Pathogenic in BRF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-26). Very rare (popmax 0.0011%, sas).

How common is BRF1 p.Ser293fs (c.876dup) in the general population?

BRF1 p.Ser293fs (c.876dup) is very rare (popmax 0.0011%, sas) (gnomAD).

BRF1 p.Ser293fs

c.876dup · rs747435524 · VCV1098377

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,080 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000992% 16/1,613,202 alleles · very rare exomes 15/1,461,142 · genomes 1/152,060 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00474%	21,103
South Asiangrpmax	0.0011%	91,080
European (non-Finnish)	0.00102%	98,333

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser293fs
Coding: c.876dup
MANE Select: NM_001519
dbSNP: rs747435524
Type: Duplication
Location: chr14:105226672 (GRCh38)
Structure: AlphaFold pLDDT 59.70 · 2 PDB
Residue 293: the 'necessary for mrna decay activation' region; the 'disordered' region

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

Similar variants

BRF1 p.Ser293= Likely benign ★★ same residue
BRF1 p.Ser293Trp Uncertain significance ★ ⚠ same residue
PACS2 p.Arg6_Leu7insArgGlySerGlyGlyAlaGlyAlaMetAlaGluArgGlyArg Uncertain significance ★ same type
PACS2 p.Gly11_Ala12insLeuProGly Uncertain significance ★ same type
PACS2 p.Leu16_Asn17insGlyAlaLeu Uncertain significance ★ same type
PACS2 p.Pro19_Val20insGlyAlaLeuAsnThrPro 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-ser293fs (accessed [today's date]).

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