Is DBT p.Arg179His (c.536G>A) pathogenic?

DBT p.Arg179His (c.536G>A) is classified Likely benign in DBT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-16). AlphaMissense: ambiguous (0.398); Ultra-rare (popmax 0.0312%, eas); Associated with maple syrup urine disease.

What condition is associated with DBT p.Arg179His (c.536G>A)?

DBT p.Arg179His (c.536G>A) is associated with maple syrup urine disease (ClinVar).

How common is DBT p.Arg179His (c.536G>A) in the general population?

DBT p.Arg179His (c.536G>A) is ultra-rare (popmax 0.0312%, eas) (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.Arg179His (c.536G>A)?

AlphaMissense predicts ambiguous (score 0.398) — an in-silico prediction, not a clinical call.

DBT p.Arg179His

c.536G>A · rs766629953 · VCV1589726

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.398 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0312%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

maple syrup urine disease

Computational evidence

Protein change
AlphaMissense	0.398	ambiguous
REVEL	0.255	benign-leaning
SaProt	LLR -9.79	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 54 kb · p 0.0036 · regional, not allelic
Overall
CADD	27.2	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 0.0312% East Asian · 14/44,880 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.00384% 62/1,613,876 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0312%	3,206
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,920
Middle Eastern	0.0164%	6,084
African / African-American	0.00534%	18,727
Admixed American	0.00333%	29,999
European (non-Finnish)	0.00305%	32,776

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.Arg179His
Coding: c.536G>A
MANE Select: NM_001918
dbSNP: rs766629953
Type: single nucleotide variant
Location: chr1:100218645 (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 179: 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.Arg179= Likely benign ★ same residue
DBT p.Arg179fs Likely pathogenic ★ same residue
DBT p.Arg179Cys 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

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-arg179his (accessed [today's date]).

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