Is BCKDK p.Pro250Ser (c.748C>T) pathogenic?

BCKDK p.Pro250Ser (c.748C>T) is classified Uncertain significance in BCKDK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-22). AlphaMissense: likely pathogenic (0.995); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with BCKDK p.Pro250Ser (c.748C>T)?

BCKDK p.Pro250Ser (c.748C>T) is associated with Inborn genetic diseases (ClinVar).

How common is BCKDK p.Pro250Ser (c.748C>T) in the general population?

BCKDK p.Pro250Ser (c.748C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about BCKDK p.Pro250Ser (c.748C>T)?

AlphaMissense predicts likely pathogenic (score 0.995) — an in-silico prediction, not a clinical call.

BCKDK p.Pro250Ser

c.748C>T · rs2544149731 · VCV2588302

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.995 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.995	likely pathogenic · top 8% in BCKDK
REVEL	0.741	pathogenic-leaning
SaProt	LLR -12.76	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	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	28.3	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 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.84e-05% 1/1,461,848 alleles · very rare

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.Pro250Ser
Coding: c.748C>T
MANE Select: NM_005881
dbSNP: rs2544149731
Type: single nucleotide variant
Location: chr16:31111122 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.03 · 5 PDB
Residue 250: 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-pro250ser (accessed [today's date]).

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