Is BCKDK p.Arg156Ter (c.466C>T) pathogenic?

BCKDK p.Arg156Ter (c.466C>T) is classified Pathogenic in BCKDK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-12). Very rare (popmax 0.00223%, eas); Associated with branched-chain keto acid dehydrogenase kinase deficiency.

What condition is associated with BCKDK p.Arg156Ter (c.466C>T)?

BCKDK p.Arg156Ter (c.466C>T) is associated with branched-chain keto acid dehydrogenase kinase deficiency (ClinVar).

How common is BCKDK p.Arg156Ter (c.466C>T) in the general population?

BCKDK p.Arg156Ter (c.466C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

BCKDK p.Arg156Ter

Q: How is Autism-epilepsy syndrome due to branched chain ketoacid dehydrogenase kinase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.466C>T · rs397514573 · VCV39743

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

branched-chain keto acid dehydrogenase kinase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 12
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP -0.068, phastCons 1
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,884 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00105% 17/1,613,888 alleles · very rare exomes 16/1,461,834 · genomes 1/152,054 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
Admixed American	0.00167%	59,986
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.00119%	84,288

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.Arg156Ter
Coding: c.466C>T
MANE Select: NM_005881
dbSNP: rs397514573
Type: single nucleotide variant
Location: chr16:31110247 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.03 · 5 PDB
Residue 156: an α-helix

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

Disease context

branched-chain keto acid dehydrogenase kinase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autism-epilepsy syndrome due to branched chain ketoacid dehydrogenase kinase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

BCKDK p.Arg156Gly Uncertain significance ★ ⚠ same residue
BCKDK c.846-3T>A Uncertain significance ★★ same condition
BCKDK p.Ala283Thr Uncertain significance ★★ ⚠ same condition
BCKDK p.Ala29Val Uncertain significance ★★ ⚠ same condition
BCKDK p.Arg177Trp Uncertain significance ★★ ⚠ same condition
BCKDK p.Ile102Thr Uncertain significance ★★ ⚠ same condition
BCKDK p.Ile122Val Uncertain significance ★★ ⚠ same condition
BCKDK p.Ile230Met 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-arg156ter (accessed [today's date]).

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