Is DBT p.Arg291Leu (c.872G>T) pathogenic?

DBT p.Arg291Leu (c.872G>T) is classified Conflicting classifications of pathogenicity in DBT (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-25). AlphaMissense: likely pathogenic (0.8415); Ultra-rare (popmax 0.01%, amr); Associated with maple syrup urine disease.

What condition is associated with DBT p.Arg291Leu (c.872G>T)?

DBT p.Arg291Leu (c.872G>T) is associated with maple syrup urine disease, maple syrup urine disease type 1A (ClinVar).

How common is DBT p.Arg291Leu (c.872G>T) in the general population?

DBT p.Arg291Leu (c.872G>T) is ultra-rare (popmax 0.01%, 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.Arg291Leu (c.872G>T)?

AlphaMissense predicts likely pathogenic (score 0.8415) — an in-silico prediction, not a clinical call.

DBT p.Arg291Leu

c.872G>T · rs775808731 · VCV457147

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8415 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

maple syrup urine disease

Computational evidence

Protein change
AlphaMissense	0.8415	likely pathogenic
REVEL	0.744	pathogenic-leaning
SaProt	LLR -12.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 54 kb · p 0.0036 · regional, not allelic
Overall
CADD	32.0	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 0.01% Admixed American · 6/59,998 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000434% 7/1,613,896 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,000
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Arg291Leu
Coding: c.872G>T
MANE Select: NM_001918
dbSNP: rs775808731
Type: single nucleotide variant
Location: chr1:100214884 (GRCh38)
Gene constraint: LOEUF 1.255 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.71 · 5 PDB
Residue 291: a binding site

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

Also linked: maple syrup urine disease type 1A

For Maple syrup urine disease (Orphanet):

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

Similar variants

DBT p.Arg291Ter Pathogenic ★★ same residue
DBT p.Arg291Gln 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
DBT p.Arg169Ter 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-arg291leu (accessed [today's date]).

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