Is DBT p.Ala422fs (c.1264dup) pathogenic?

DBT p.Ala422fs (c.1264dup) is classified Pathogenic in DBT (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-14). Very rare (popmax 8.49e-05%, nfe); Associated with maple syrup urine disease.

What condition is associated with DBT p.Ala422fs (c.1264dup)?

DBT p.Ala422fs (c.1264dup) is associated with maple syrup urine disease (ClinVar).

How common is DBT p.Ala422fs (c.1264dup) in the general population?

DBT p.Ala422fs (c.1264dup) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

How is Maple syrup urine disease inherited?

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

DBT p.Ala422fs

c.1264dup · rs1401829291 · VCV844162

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Conditions

maple syrup urine disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (10 of 11, 16 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.9	GERP 2, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,178,418 alleles

Overall 6.85e-05% 1/1,460,134 alleles · very rare

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.Ala422fs
Coding: c.1264dup
MANE Select: NM_001918
dbSNP: rs1401829291
Type: Duplication
Location: chr1:100206246 (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 — 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

DBT p.Ala422Thr Uncertain significance ★ ⚠ same residue
DBT p.His49fs Pathogenic/Likely pathogenic ★★ same condition
DBT p.Asn28dup Uncertain significance ★★ same condition
DBT c.1282-24_1282-10dup Benign/Likely benign ★★ same condition
DBT c.251+19dup Benign/Likely benign ★★ same condition
DBT p.Asn361fs Pathogenic ★ same condition
DBT p.Ile186fs Pathogenic ★ same condition
DBT p.Leu217fs 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-ala422fs (accessed [today's date]).

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