Is BCKDK p.Arg197Ser (c.591G>T) pathogenic?

BCKDK p.Arg197Ser (c.591G>T) is classified Uncertain significance in BCKDK (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-01). AlphaMissense: likely pathogenic (0.9967); Very rare (popmax 0.00133%, afr).

How common is BCKDK p.Arg197Ser (c.591G>T) in the general population?

BCKDK p.Arg197Ser (c.591G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about BCKDK p.Arg197Ser (c.591G>T)?

AlphaMissense predicts likely pathogenic (score 0.9967) — an in-silico prediction, not a clinical call.

BCKDK p.Arg197Ser

c.591G>T · rs2143941358 · VCV1176350

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9967 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9967	likely pathogenic · top 6% in BCKDK
REVEL	0.456	indeterminate
SaProt	LLR -14.35	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -1.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 3,038 bp · p 4.5e-05 · regional, not allelic
Overall
CADD	23.4	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 0.00133% African / African-American · 1/75,040 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,920 alleles · very rare exomes 5/1,461,630 · genomes 0/152,290 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,040
European (non-Finnish)	0.000339%	295,010

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.Arg197Ser
Coding: c.591G>T
MANE Select: NM_005881
dbSNP: rs2143941358
Type: single nucleotide variant
Location: chr16:31110448 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.03 · 5 PDB
Residue 197: the histidine kinase domain; an α-helix

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

Similar variants

BCKDK p.Arg156Ter Pathogenic ★★ same type
BCKDK c.846-3T>A Uncertain significance ★★ same type
BCKDK p.Ala283Thr Uncertain significance ★★ ⚠ same type
BCKDK p.Ala29Val Uncertain significance ★★ ⚠ same type
BCKDK p.Arg177Trp Uncertain significance ★★ ⚠ same type
BCKDK p.Arg224Cys Uncertain significance ★★ ⚠ same type
BCKDK p.Arg406Gly Uncertain significance ★★ ⚠ same type
BCKDK p.Gln341Lys 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-arg197ser (accessed [today's date]).

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