Is DBT p.Glu437Lys (c.1309G>A) pathogenic?

DBT p.Glu437Lys (c.1309G>A) is classified Conflicting classifications of pathogenicity in DBT (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.1123); Ultra-rare (popmax 0.0503%, amr); Associated with maple syrup urine disease type 1A.

What condition is associated with DBT p.Glu437Lys (c.1309G>A)?

DBT p.Glu437Lys (c.1309G>A) is associated with maple syrup urine disease type 1A, maple syrup urine disease (ClinVar).

How common is DBT p.Glu437Lys (c.1309G>A) in the general population?

DBT p.Glu437Lys (c.1309G>A) is ultra-rare (popmax 0.0503%, 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.Glu437Lys (c.1309G>A)?

AlphaMissense predicts likely benign (score 0.1123) — an in-silico prediction, not a clinical call.

DBT p.Glu437Lys

c.1309G>A · rs772490888 · VCV1560181

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1123 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0503%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

maple syrup urine disease type 1A

Computational evidence

Protein change
AlphaMissense	0.1123	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -12.32	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 54 kb · p 0.0036 · regional, not allelic
Overall
CADD	22.4	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 0.0503% Admixed American · 26/51,664 alleles

Filtering AF 0.0352% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0302%

Overall 0.00207% 27/1,303,732 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0503%	1,987
European (non-Finnish)	0.000106%	939,488

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.Glu437Lys
Coding: c.1309G>A
MANE Select: NM_001918
dbSNP: rs772490888
Type: single nucleotide variant
Location: chr1:100196395 (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 1A — 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 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
DBT p.Arg291Ter Pathogenic ★★ same condition
DBT p.Arg301Cys 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-glu437lys (accessed [today's date]).

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