Is BCKDK p.Ala338Asp (c.1013C>A) pathogenic?

BCKDK p.Ala338Asp (c.1013C>A) is classified Uncertain significance in BCKDK (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-01). AlphaMissense: likely benign (0.1931); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with BCKDK p.Ala338Asp (c.1013C>A)?

BCKDK p.Ala338Asp (c.1013C>A) is associated with Inborn genetic diseases (ClinVar).

How common is BCKDK p.Ala338Asp (c.1013C>A) in the general population?

BCKDK p.Ala338Asp (c.1013C>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about BCKDK p.Ala338Asp (c.1013C>A)?

AlphaMissense predicts likely benign (score 0.1931) — an in-silico prediction, not a clinical call.

BCKDK p.Ala338Asp

c.1013C>A · rs1399877339 · VCV2230089

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1931 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1931	likely benign
REVEL	0.264	benign-leaning
SaProt	LLR -6.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.57 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	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	21.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00031% 5/1,614,162 alleles · ultra-rare exomes 4/1,461,860 · genomes 1/152,302 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000254%	393,343

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.Ala338Asp
Coding: c.1013C>A
MANE Select: NM_005881
dbSNP: rs1399877339
Type: single nucleotide variant
Location: chr16:31111946 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.03 · 5 PDB
Residue 338: 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-ala338asp (accessed [today's date]).

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