Is BCKDK p.Val125Met (c.373G>A) pathogenic?

BCKDK p.Val125Met (c.373G>A) is classified Uncertain significance in BCKDK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-21). AlphaMissense: likely pathogenic (0.9608); Ultra-rare (popmax 0.0132%, nfe); Associated with branched-chain keto acid dehydrogenase kinase deficiency.

What condition is associated with BCKDK p.Val125Met (c.373G>A)?

BCKDK p.Val125Met (c.373G>A) is associated with branched-chain keto acid dehydrogenase kinase deficiency (ClinVar).

How common is BCKDK p.Val125Met (c.373G>A) in the general population?

BCKDK p.Val125Met (c.373G>A) is ultra-rare (popmax 0.0132%, nfe) (gnomAD).

What do computational predictors say about BCKDK p.Val125Met (c.373G>A)?

AlphaMissense predicts likely pathogenic (score 0.9608) — an in-silico prediction, not a clinical call.

BCKDK p.Val125Met

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.373G>A · rs141282419 · VCV197262

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9608 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

branched-chain keto acid dehydrogenase kinase deficiency

Computational evidence

Protein change
AlphaMissense	0.9608	likely pathogenic
REVEL	0.407	indeterminate
SaProt	LLR -12.24	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.22	donor loss, 7 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 3,038 bp · p 4.5e-05 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0132% European (non-Finnish) · 156/1,179,910 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0108%

Overall 0.00998% 161/1,613,498 alleles · ultra-rare exomes 152/1,461,324 · genomes 9/152,174 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0132%	7,564
East Asian	0.00445%	22,447
Remaining individualsnot grpmax-eligible	0.0032%	31,238
Finnishnot grpmax-eligible	0.00157%	63,612

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.Val125Met
Coding: c.373G>A
MANE Select: NM_005881
dbSNP: rs141282419
Type: single nucleotide variant
Location: chr16:31109781 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.03 · 5 PDB
Residue 125: 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.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
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-val125met (accessed [today's date]).

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