Is BRF2 p.Arg74Gln (c.221G>A) pathogenic?

BRF2 p.Arg74Gln (c.221G>A) is classified Uncertain significance in BRF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely benign (0.082); Very rare (popmax 0.00314%, nfe).

How common is BRF2 p.Arg74Gln (c.221G>A) in the general population?

BRF2 p.Arg74Gln (c.221G>A) is very rare (popmax 0.00314%, nfe) (gnomAD).

What do computational predictors say about BRF2 p.Arg74Gln (c.221G>A)?

AlphaMissense predicts likely benign (score 0.082) — an in-silico prediction, not a clinical call.

BRF2 p.Arg74Gln

c.221G>A · rs138178332 · VCV2522393

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.082 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.082	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -5.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 1.5, phastCons 1
Overall
CADD	20.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00314% European (non-Finnish) · 37/1,179,240 alleles

Filtering AF 0.00232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00242% 39/1,613,080 alleles · very rare exomes 35/1,460,934 · genomes 4/152,146 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00314%	31,871
Remaining individualsnot grpmax-eligible	0.0016%	62,466
South Asian	0.0011%	91,062

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: BRF2
Protein: p.Arg74Gln
Coding: c.221G>A
MANE Select: NM_018310
dbSNP: rs138178332
Type: single nucleotide variant
Location: chr8:37847169 (GRCh38)
Gene constraint: LOEUF 0.827 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.79 · 22 PDB
Residue 74: an α-helix

Full BRF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BRF2 p.Ala109Thr Uncertain significance ★ ⚠ same type
BRF2 p.Ala185Pro Uncertain significance ★ ⚠ same type
BRF2 p.Ala262Val Uncertain significance ★ ⚠ same type
BRF2 p.Ala93Thr Uncertain significance ★ ⚠ same type
BRF2 p.Arg102Trp Uncertain significance ★ ⚠ same type
BRF2 p.Arg127Gln Uncertain significance ★ ⚠ same type
BRF2 p.Arg203Gln Uncertain significance ★ ⚠ same type
BRF2 p.Arg265His 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/brf2-p-arg74gln (accessed [today's date]).

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