Is DBT p.Arg462Cys (c.1384C>T) pathogenic?

DBT p.Arg462Cys (c.1384C>T) is classified Likely pathogenic in DBT (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-14). AlphaMissense: likely benign (0.258); Ultra-rare (popmax 0.0165%, mid); Associated with maple syrup urine disease.

What condition is associated with DBT p.Arg462Cys (c.1384C>T)?

DBT p.Arg462Cys (c.1384C>T) is associated with maple syrup urine disease (ClinVar).

How common is DBT p.Arg462Cys (c.1384C>T) in the general population?

DBT p.Arg462Cys (c.1384C>T) is ultra-rare (popmax 0.0165%, 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.Arg462Cys (c.1384C>T)?

AlphaMissense predicts likely benign (score 0.258) — an in-silico prediction, not a clinical call.

DBT p.Arg462Cys

c.1384C>T · rs765257706 · VCV1505569

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.258 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

maple syrup urine disease

Computational evidence

Protein change
AlphaMissense	0.258	likely benign ⚠ discordant with ClinVar
REVEL	0.577	indeterminate
SaProt	LLR -12.72	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 54 kb · p 0.0036 · regional, not allelic
Overall
CADD	33.0	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 0.0165% Middle Eastern · 1/6,074 alleles

Filtering AF 0.000741% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000745% 12/1,611,524 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,074
East Asian	0.00447%	22,371
South Asian	0.0022%	45,513
Admixed American	0.00168%	59,650
European (non-Finnish)	0.000509%	196,593

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.Arg462Cys
Coding: c.1384C>T
MANE Select: NM_001918
dbSNP: rs765257706
Type: single nucleotide variant
Location: chr1:100196320 (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.Arg462Pro Pathogenic ★★ same residue
DBT p.Arg462His Uncertain significance ★ ⚠ same residue
DBT p.Arg462fs Likely 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
DBT c.52-1G>A 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-arg462cys (accessed [today's date]).

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