Is BCKDHA p.Phe409Val (c.1225T>G) pathogenic?

BCKDHA p.Phe409Val (c.1225T>G) is classified Uncertain significance in BCKDHA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-02-25). AlphaMissense: likely pathogenic (0.8412); Absent from gnomAD v4.1; Associated with maple syrup urine disease type 1A.

What condition is associated with BCKDHA p.Phe409Val (c.1225T>G)?

BCKDHA p.Phe409Val (c.1225T>G) is associated with maple syrup urine disease type 1A (ClinVar).

How common is BCKDHA p.Phe409Val (c.1225T>G) in the general population?

BCKDHA p.Phe409Val (c.1225T>G) is absent from gnomAD v4.1 (gnomAD).

How is Maple syrup urine disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BCKDHA p.Phe409Val (c.1225T>G)?

AlphaMissense predicts likely pathogenic (score 0.8412) — an in-silico prediction, not a clinical call.

BCKDHA p.Phe409Val

c.1225T>G · VCV4063804

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8412 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

maple syrup urine disease type 1A

Computational evidence

Protein change
AlphaMissense	0.8412	likely pathogenic
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -12.63	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.48	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 7.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 27 kb · p 0.00015 · regional, not allelic
Overall
CADD	28.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BCKDHA
Protein: p.Phe409Val
Coding: c.1225T>G
MANE Select: NM_000709
Type: single nucleotide variant
Location: chr19:41424495 (GRCh38)
Gene constraint: LOEUF 1.086 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.82 · 24 PDB
Residue 409: a UniProt-annotated variant site (in msud1a; decreased solubility; loss of mitochondrial alpha-ketoglutarate dehydrogenase complex assembly; loss of 3-methyl-2-oxobutanoate dehydrogenase activity); a turn

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

Disease context

maple syrup urine disease type 1A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Maple syrup urine disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

BCKDHA p.Phe409Cys Pathogenic/Likely pathogenic ★★ same residue
BCKDHA p.Phe409Leu Likely pathogenic ★ same residue
BCKDHA c.1168-1G>A Likely pathogenic ★★ same condition
BCKDHA c.1168-2A>G Pathogenic/Likely pathogenic ★★ same condition
BCKDHA c.288+1G>A Pathogenic ★★ same condition
BCKDHA c.288+9C>T Pathogenic/Likely pathogenic ★★ same condition
BCKDHA c.376-2A>G Likely pathogenic ★★ same condition
BCKDHA c.647-1G>C Pathogenic/Likely pathogenic ★★ 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/bckdha-p-phe409val (accessed [today's date]).

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