Is DBT p.Arg462Pro (c.1385G>C) pathogenic?

DBT p.Arg462Pro (c.1385G>C) is classified Pathogenic in DBT (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-08-12). AlphaMissense: likely pathogenic (0.9913); Very rare (popmax 0.00844%, amr); Associated with maple syrup urine disease type 2.

What condition is associated with DBT p.Arg462Pro (c.1385G>C)?

DBT p.Arg462Pro (c.1385G>C) is associated with maple syrup urine disease type 2, maple syrup urine disease (ClinVar).

How common is DBT p.Arg462Pro (c.1385G>C) in the general population?

DBT p.Arg462Pro (c.1385G>C) is very rare (popmax 0.00844%, amr) (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.Arg462Pro (c.1385G>C)?

AlphaMissense predicts likely pathogenic (score 0.9913) — an in-silico prediction, not a clinical call.

DBT p.Arg462Pro

c.1385G>C · rs750594890 · VCV1407245

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9913 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00844%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

maple syrup urine disease type 2

Computational evidence

Protein change
AlphaMissense	0.9913	likely pathogenic ✓ concordant with ClinVar · top 4% in DBT
REVEL	0.622	indeterminate
SaProt	LLR -16.79	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 54 kb · p 0.0036 · regional, not allelic
Overall
CADD	26.1	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 0.00844% Admixed American · 5/59,256 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00209%

Overall 0.000342% 5/1,461,516 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.Arg462Pro
Coding: c.1385G>C
MANE Select: NM_001918
dbSNP: rs750594890
Type: single nucleotide variant
Location: chr1:100196319 (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 type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: maple syrup urine disease

For Maple syrup urine disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

DBT p.Arg462Cys Likely 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-arg462pro (accessed [today's date]).

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