Is BRF2 p.Val35Leu (c.103G>C) pathogenic?

BRF2 p.Val35Leu (c.103G>C) is classified Uncertain significance in BRF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-02). AlphaMissense: likely benign (0.122); Rare (popmax 0.13%, nfe).

How common is BRF2 p.Val35Leu (c.103G>C) in the general population?

BRF2 p.Val35Leu (c.103G>C) is rare (popmax 0.13%, nfe) (gnomAD).

What do computational predictors say about BRF2 p.Val35Leu (c.103G>C)?

AlphaMissense predicts likely benign (score 0.122) — an in-silico prediction, not a clinical call.

BRF2 p.Val35Leu

c.103G>C · rs138044288 · VCV3135036

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.122 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.13%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.122	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -4.92	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	GERP -1.6, phastCons 0.99
Overall
CADD	13.83	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 0.13% European (non-Finnish) · 1,532/1,179,930 alleles

Filtering AF 0.124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.122%

Overall 0.1% 1,616/1,613,570 alleles · rare exomes 1,528/1,461,378 · genomes 88/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.13%	770
Remaining individualsnot grpmax-eligible	0.0928%	1,077
Finnishnot grpmax-eligible	0.0173%	5,789
Middle Eastern	0.0164%	6,084
African / African-American	0.016%	6,243
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Admixed American	0.00167%	59,998

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.Val35Leu
Coding: c.103G>C
MANE Select: NM_018310
dbSNP: rs138044288
Type: single nucleotide variant
Location: chr8:37849681 (GRCh38)
Gene constraint: LOEUF 0.827 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.79 · 22 PDB
Residue 35: a β-strand

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-val35leu (accessed [today's date]).

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