Is BRF2 p.Pro2Ser (c.4C>T) pathogenic?

BRF2 p.Pro2Ser (c.4C>T) is classified Uncertain significance in BRF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely benign (0.0748); Very rare (popmax 0.00492%, nfe).

How common is BRF2 p.Pro2Ser (c.4C>T) in the general population?

BRF2 p.Pro2Ser (c.4C>T) is very rare (popmax 0.00492%, nfe) (gnomAD).

What do computational predictors say about BRF2 p.Pro2Ser (c.4C>T)?

AlphaMissense predicts likely benign (score 0.0748) — an in-silico prediction, not a clinical call.

BRF2 p.Pro2Ser

c.4C>T · VCV4216155

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0748 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00492%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0748	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -5.20	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 1.7	GERP 0.62, phastCons 1
Overall
CADD	16.16	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 0.00492% European (non-Finnish) · 58/1,178,392 alleles

Filtering AF 0.00386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00353%

Overall 0.00367% 59/1,607,656 alleles · very rare exomes 58/1,455,402 · genomes 1/152,254 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00492%	20,317
Remaining individualsnot grpmax-eligible	0.00161%	62,220

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.Pro2Ser
Coding: c.4C>T
MANE Select: NM_018310
Type: single nucleotide variant
Location: chr8:37849780 (GRCh38)
Gene constraint: LOEUF 0.827 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.79 · 22 PDB

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-pro2ser (accessed [today's date]).

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