Is DBT p.Lys222fs (c.663_670del) pathogenic?

DBT p.Lys222fs (c.663670del) is classified Pathogenic in DBT (ClinVar, Single submitter, 1 submitter; last evaluated 2017-12-30). Very rare (popmax 0.0011%, sas); Associated with maple syrup urine disease.

What condition is associated with DBT p.Lys222fs (c.663_670del)?

DBT p.Lys222fs (c.663_670del) is associated with maple syrup urine disease (ClinVar).

How common is DBT p.Lys222fs (c.663_670del) in the general population?

DBT p.Lys222fs (c.663_670del) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Maple syrup urine disease inherited?

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

DBT p.Lys222fs

c.663_670del · rs748851630 · VCV623328

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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	predicted	premature termination codon in exon 6 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,080 alleles

Overall 6.84e-05% 1/1,461,576 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.Lys222fs
Coding: c.663_670del
MANE Select: NM_001918
dbSNP: rs748851630
Type: Deletion
Location: chr1:100216085 (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.Lys222= Likely benign ★ same residue
DBT c.434-15_434-4del Pathogenic/Likely pathogenic ★★ same condition
DBT p.Cys26fs Pathogenic ★★ same condition
DBT p.Phe276fs Pathogenic/Likely pathogenic ★★ same condition
DBT p.Thr153fs Pathogenic/Likely pathogenic ★★ same condition
DBT p.Thr388_Thr389insTer Likely pathogenic ★★ same condition
DBT p.Thr91fs Pathogenic ★★ same condition
DBT c.1210-10_1210-9del Benign ★★ 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-lys222fs (accessed [today's date]).

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