Is BCKDK p.Arg374Trp (c.1120C>T) pathogenic?

BCKDK p.Arg374Trp (c.1120C>T) is classified Conflicting classifications of pathogenicity in BCKDK (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2021-05-14). AlphaMissense: likely pathogenic (0.5991); Very rare (popmax 0.00223%, eas); Associated with BCKDK-related disorder.

What condition is associated with BCKDK p.Arg374Trp (c.1120C>T)?

BCKDK p.Arg374Trp (c.1120C>T) is associated with BCKDK-related disorder (ClinVar).

How common is BCKDK p.Arg374Trp (c.1120C>T) in the general population?

BCKDK p.Arg374Trp (c.1120C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about BCKDK p.Arg374Trp (c.1120C>T)?

AlphaMissense predicts likely pathogenic (score 0.5991) — an in-silico prediction, not a clinical call.

BCKDK p.Arg374Trp

c.1120C>T · rs781432488 · VCV502614

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

BCKDK-related disorder

Computational evidence

Protein change
AlphaMissense	0.5991	likely pathogenic
REVEL	0.589	indeterminate
SaProt	LLR -13.84	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.3	GERP -0.12, phastCons 0.61
Regional constraint	o/e 0.83	unconstrained · MANE · 3,038 bp · p 4.5e-05 · regional, not allelic
Overall
CADD	26.4	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 0.00223% East Asian · 1/44,836 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00031% 5/1,612,218 alleles · very rare exomes 3/1,460,014 · genomes 2/152,204 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,836
African / African-American	0.00134%	74,906
South Asian	0.0011%	91,006
European (non-Finnish)	0.00017%	589,501

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.Arg374Trp
Coding: c.1120C>T
MANE Select: NM_005881
dbSNP: rs781432488
Type: single nucleotide variant
Location: chr16:31112146 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.03 · 5 PDB
Residue 374: the histidine kinase domain; an α-helix

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

Disease context

BCKDK-related disorder

Similar variants

BCKDK p.Ile116Asn Pathogenic ★ same condition
BCKDK c.424-6C>G Uncertain significance ★ same condition
BCKDK p.Thr372Arg Uncertain significance ★ ⚠ same condition
BCKDK c.642+10T>A Likely benign same condition
BCKDK c.845+6G>A Likely benign same condition
BCKDK p.Thr35fs Likely pathogenic ★ same condition
BCKDK p.Arg156Ter Pathogenic ★★ same type
BCKDK c.846-3T>A 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/bckdk-p-arg374trp (accessed [today's date]).

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