Is DBT p.Gln321Leu (c.962A>T) pathogenic?

DBT p.Gln321Leu (c.962A>T) is classified Uncertain significance in DBT (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-20). AlphaMissense: likely benign (0.1989); Very rare (popmax 0.000339%, nfe); Associated with maple syrup urine disease.

What condition is associated with DBT p.Gln321Leu (c.962A>T)?

DBT p.Gln321Leu (c.962A>T) is associated with maple syrup urine disease (ClinVar).

How common is DBT p.Gln321Leu (c.962A>T) in the general population?

DBT p.Gln321Leu (c.962A>T) is very rare (popmax 0.000339%, nfe) (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 DBT p.Gln321Leu (c.962A>T)?

AlphaMissense predicts likely benign (score 0.1989) — an in-silico prediction, not a clinical call.

DBT p.Gln321Leu

c.962A>T · rs758048048 · VCV1043079

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

maple syrup urine disease

Computational evidence

Protein change
AlphaMissense	0.1989	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -12.09	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 54 kb · p 0.0036 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,738 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,464 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.Gln321Leu
Coding: c.962A>T
MANE Select: NM_001918
dbSNP: rs758048048
Type: single nucleotide variant
Location: chr1:100210749 (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.Gln321Ter Pathogenic/Likely pathogenic ★★ same residue
DBT p.Gln321His Uncertain significance ★ ⚠ same residue
DBT p.Gln321= Likely benign ★ same residue
DBT p.Gln321fs Pathogenic ★ 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

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-gln321leu (accessed [today's date]).

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