Is BCKDK p.Arg406= (c.1218G>A) pathogenic?

BCKDK p.Arg406= (c.1218G>A) is classified Conflicting classifications of pathogenicity in BCKDK (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-20). Ultra-rare (popmax 0.082%, nfe); Associated with branched-chain keto acid dehydrogenase kinase deficiency.

What condition is associated with BCKDK p.Arg406= (c.1218G>A)?

BCKDK p.Arg406= (c.1218G>A) is associated with branched-chain keto acid dehydrogenase kinase deficiency (ClinVar).

How common is BCKDK p.Arg406= (c.1218G>A) in the general population?

BCKDK p.Arg406= (c.1218G>A) is ultra-rare (popmax 0.082%, nfe) (gnomAD).

BCKDK p.Arg406=

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.1218G>A · rs145180240 · VCV194067

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.082%, nfe)

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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -4.3, phastCons 1
Overall
CADD	7.265	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.082% European (non-Finnish) · 968/1,179,980 alleles

Filtering AF 0.0777% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.076%

Overall 0.0679% 1,094/1,610,348 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.082%	1,219
Remaining individualsnot grpmax-eligible	0.072%	1,388
Ashkenazi Jewishnot grpmax-eligible	0.0709%	1,410
Finnishnot grpmax-eligible	0.0498%	2,009
Middle Eastern	0.033%	3,030
Admixed American	0.02%	5,003
African / African-American	0.0186%	5,362
South Asian	0.0022%	45,543

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.Arg406=
Coding: c.1218G>A
MANE Select: NM_005881
dbSNP: rs145180240
Type: single nucleotide variant
Location: chr16:31112244 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.03 · 5 PDB

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.Arg406Gly Uncertain significance ★★ ⚠ same residue
BCKDK p.Arg406Gln Uncertain significance ★ ⚠ same residue
BCKDK p.Arg156Ter Pathogenic ★★ same condition
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

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-arg406 (accessed [today's date]).

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