Is DBT p.Gln321His (c.963G>C) pathogenic?

DBT p.Gln321His (c.963G>C) is classified Uncertain significance in DBT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-11). AlphaMissense: likely benign (0.127); Ultra-rare (popmax 0.0164%, mid); Associated with maple syrup urine disease.

What condition is associated with DBT p.Gln321His (c.963G>C)?

DBT p.Gln321His (c.963G>C) is associated with maple syrup urine disease (ClinVar).

How common is DBT p.Gln321His (c.963G>C) in the general population?

DBT p.Gln321His (c.963G>C) is ultra-rare (popmax 0.0164%, mid) (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.Gln321His (c.963G>C)?

AlphaMissense predicts likely benign (score 0.127) — an in-silico prediction, not a clinical call.

DBT p.Gln321His

c.963G>C · rs762063921 · VCV1979680

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.127 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

maple syrup urine disease

Computational evidence

Protein change
AlphaMissense	0.127	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -7.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.55	GERP 1.1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 54 kb · p 0.0036 · regional, not allelic
Overall
CADD	17.91	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00211% 34/1,613,552 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
Admixed American	0.00833%	12,000
Remaining individualsnot grpmax-eligible	0.0064%	15,615
European (non-Finnish)	0.00195%	51,293
African / African-American	0.00134%	74,878

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.Gln321His
Coding: c.963G>C
MANE Select: NM_001918
dbSNP: rs762063921
Type: single nucleotide variant
Location: chr1:100210748 (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.Gln321Leu 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-gln321his (accessed [today's date]).

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