Is BRF1 p.Asp349His (c.1045G>C) pathogenic?

BRF1 p.Asp349His (c.1045G>C) is classified Uncertain significance in BRF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.1423); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with BRF1 p.Asp349His (c.1045G>C)?

BRF1 p.Asp349His (c.1045G>C) is associated with Inborn genetic diseases (ClinVar).

How common is BRF1 p.Asp349His (c.1045G>C) in the general population?

BRF1 p.Asp349His (c.1045G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about BRF1 p.Asp349His (c.1045G>C)?

AlphaMissense predicts likely benign (score 0.1423) — an in-silico prediction, not a clinical call.

BRF1 p.Asp349His

c.1045G>C · VCV4216144

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1423 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1423	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -7.49	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 5.8	GERP 1.7, phastCons 1
Overall
CADD	21.3	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 0.00133% African / African-American · 1/75,028 alleles

Overall 0.000137% 2/1,461,322 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,028
European (non-Finnish)	8.48e-05%	1,179,894

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.Asp349His
Coding: c.1045G>C
MANE Select: NM_004926 · reported on NM_001519
Type: single nucleotide variant
Location: chr14:105226072 (GRCh38)
Structure: AlphaFold pLDDT 59.70 · 2 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BTBD6 p.Gly349Ser Uncertain significance ★ same residue
BRF1 p.Ala565Ser Uncertain significance ★★ ⚠ same condition
BRF1 p.Arg213Lys Uncertain significance ★★ ⚠ same condition
BRF1 p.Arg216Gln Uncertain significance ★★ ⚠ same condition
BRF1 p.Arg261Gln Uncertain significance ★★ ⚠ same condition
BRF1 p.Arg302Trp Uncertain significance ★★ ⚠ same condition
BRF1 p.Gly402Ser Uncertain significance ★★ ⚠ same condition
BRF1 p.Leu138Pro Uncertain significance ★★ ⚠ same condition

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-asp349his (accessed [today's date]).

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