Is BCKDHA p.Pro417= (c.1251C>T) pathogenic?

BCKDHA p.Pro417= (c.1251C>T) is classified Conflicting classifications of pathogenicity in BCKDHA (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.0308%, nfe); Associated with Inborn genetic diseases.

What condition is associated with BCKDHA p.Pro417= (c.1251C>T)?

BCKDHA p.Pro417= (c.1251C>T) is associated with Inborn genetic diseases, maple syrup urine disease (ClinVar).

How common is BCKDHA p.Pro417= (c.1251C>T) in the general population?

BCKDHA p.Pro417= (c.1251C>T) is ultra-rare (popmax 0.0308%, nfe) (gnomAD).

BCKDHA p.Pro417=

c.1251C>T · rs147021347 · VCV166742

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0308%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.4	GERP -3.4
Overall
CADD	3.423	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0308% European (non-Finnish) · 363/1,180,004 alleles

Filtering AF 0.0281% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0271%

Overall 0.0246% 397/1,614,118 alleles · ultra-rare exomes 365/1,461,848 · genomes 32/152,270 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0308%	3,251
Remaining individualsnot grpmax-eligible	0.024%	4,167
Middle Eastern	0.0165%	6,062
Admixed American	0.0133%	7,504
African / African-American	0.008%	12,504
East Asian	0.00446%	22,438
Finnishnot grpmax-eligible	0.00156%	64,030
South Asian	0.0011%	91,076

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: BCKDHA
Protein: p.Pro417=
Coding: c.1251C>T
MANE Select: NM_000709
dbSNP: rs147021347
Type: single nucleotide variant
Location: chr19:41424521 (GRCh38)
Gene constraint: LOEUF 1.086 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.82 · 24 PDB

Full BCKDHA 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

Also linked: maple syrup urine disease

Similar variants

BCKDHA c.109-1G>A Pathogenic/Likely pathogenic ★★ same condition
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
BCKDHA c.853+2T>C 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-pro417 (accessed [today's date]).

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