Is BCKDK p.Arg261Trp (c.781C>T) pathogenic?

BCKDK p.Arg261Trp (c.781C>T) is classified Uncertain significance in BCKDK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-09). AlphaMissense: ambiguous (0.5106); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with BCKDK p.Arg261Trp (c.781C>T)?

BCKDK p.Arg261Trp (c.781C>T) is associated with Inborn genetic diseases (ClinVar).

How common is BCKDK p.Arg261Trp (c.781C>T) in the general population?

BCKDK p.Arg261Trp (c.781C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about BCKDK p.Arg261Trp (c.781C>T)?

AlphaMissense predicts ambiguous (score 0.5106) — an in-silico prediction, not a clinical call.

BCKDK p.Arg261Trp

c.781C>T · VCV3823584

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5106 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5106	ambiguous
REVEL	0.556	indeterminate
SaProt	LLR -12.19	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 3,038 bp · p 4.5e-05 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,002 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00124% 20/1,614,156 alleles · very rare exomes 20/1,461,868 · genomes 0/152,288 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,002
European (non-Finnish)	0.00161%	62,106

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: BCKDK
Protein: p.Arg261Trp
Coding: c.781C>T
MANE Select: NM_005881
Type: single nucleotide variant
Location: chr16:31111155 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.03 · 5 PDB
Residue 261: the histidine kinase domain

Full BCKDK 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

BCKDK c.846-3T>A Uncertain significance ★★ same condition
BCKDK p.Arg177Trp Uncertain significance ★★ ⚠ same condition
BCKDK p.Arg224Cys Uncertain significance ★★ ⚠ same condition
BCKDK p.Arg406Gly Uncertain significance ★★ ⚠ same condition
BCKDK p.Gln341Lys Uncertain significance ★★ ⚠ same condition
BCKDK p.Lys163Arg Uncertain significance ★★ ⚠ same condition
BCKDK p.Lys184Asn Uncertain significance ★★ ⚠ same condition
BCKDK p.Pro141Leu 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/bckdk-p-arg261trp (accessed [today's date]).

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