Is DBT p.Arg178His (c.533G>A) pathogenic?

DBT p.Arg178His (c.533G>A) is classified Uncertain significance in DBT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-09). AlphaMissense: likely pathogenic (0.8896); Very rare (popmax 0.00401%, afr); Associated with maple syrup urine disease.

What condition is associated with DBT p.Arg178His (c.533G>A)?

DBT p.Arg178His (c.533G>A) is associated with maple syrup urine disease (ClinVar).

How common is DBT p.Arg178His (c.533G>A) in the general population?

DBT p.Arg178His (c.533G>A) is very rare (popmax 0.00401%, afr) (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.Arg178His (c.533G>A)?

AlphaMissense predicts likely pathogenic (score 0.8896) — an in-silico prediction, not a clinical call.

DBT p.Arg178His

c.533G>A · rs139251881 · VCV2157270

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8896 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

maple syrup urine disease

Computational evidence

Protein change
AlphaMissense	0.8896	likely pathogenic
REVEL	0.552	indeterminate
SaProt	LLR -12.97	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 5.9	GERP 1.9, 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

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00401% African / African-American · 3/74,866 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00161% 26/1,613,760 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,955
Remaining individualsnot grpmax-eligible	0.0032%	31,239
European (non-Finnish)	0.0017%	58,995
South Asian	0.0011%	91,070

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.Arg178His
Coding: c.533G>A
MANE Select: NM_001918
dbSNP: rs139251881
Type: single nucleotide variant
Location: chr1:100218648 (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 178: the peripheral subunit-binding (psbd) domain; an α-helix

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.Arg178fs Pathogenic ★ same residue
DBT p.Arg178Cys Uncertain significance ★ ⚠ 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.Arg291Ter 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-arg178his (accessed [today's date]).

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