Is DBT p.Arg431Ter (c.1291C>T) pathogenic?

DBT p.Arg431Ter (c.1291C>T) is classified Pathogenic in DBT (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-04-27). Very rare (popmax 0.00785%, eas); Associated with maple syrup urine disease type 1A.

What condition is associated with DBT p.Arg431Ter (c.1291C>T)?

DBT p.Arg431Ter (c.1291C>T) is associated with maple syrup urine disease type 1A, maple syrup urine disease, maple syrup urine disease type 2 (ClinVar).

How common is DBT p.Arg431Ter (c.1291C>T) in the general population?

DBT p.Arg431Ter (c.1291C>T) is very rare (popmax 0.00785%, eas) (gnomAD).

How is Maple syrup urine disease inherited?

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

DBT p.Arg431Ter

c.1291C>T · rs398123660 · VCV93991

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00785%, eas)

Conditions

maple syrup urine disease type 1A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (11 of 11) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.29	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 5	GERP 1.1, phastCons 1
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00785% East Asian · 2/25,466 alleles

Filtering AF 0.00195% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00111%

Overall 0.00159% 11/691,088 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00785%	12,733
South Asian	0.00579%	17,258
Finnishnot grpmax-eligible	0.00455%	21,992
Remaining individualsnot grpmax-eligible	0.00365%	27,394
European (non-Finnish)	0.00048%	208,432

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: DBT
Protein: p.Arg431Ter
Coding: c.1291C>T
MANE Select: NM_001918
dbSNP: rs398123660
Type: single nucleotide variant
Location: chr1:100196413 (GRCh38)
Gene constraint: LOEUF 1.255 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.71 · 5 PDB

Full DBT 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

Also linked: maple syrup urine disease maple syrup urine disease type 2

For Maple syrup urine disease (Orphanet):

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

Similar variants

DBT p.Arg431Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
DBT c.1018-550A>G Pathogenic/Likely pathogenic ★★ same condition
DBT c.1281+1G>A Pathogenic/Likely pathogenic ★★ same condition
DBT c.1281+1G>T Pathogenic/Likely pathogenic ★★ same condition
DBT c.51+1G>T Pathogenic/Likely pathogenic ★★ same condition
DBT c.52-1G>A Pathogenic/Likely pathogenic ★★ same condition
DBT c.773-2A>G Pathogenic ★★ same condition
DBT p.Arg169Ter 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/dbt-p-arg431ter (accessed [today's date]).

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