Is DBT p.Phe276Cys (c.827T>G) pathogenic?

DBT p.Phe276Cys (c.827T>G) is classified Pathogenic/Likely pathogenic in DBT (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-01-25). AlphaMissense: likely pathogenic (0.8791); Ultra-rare (popmax 0.0257%, nfe); Associated with DBT-related disorder.

What condition is associated with DBT p.Phe276Cys (c.827T>G)?

DBT p.Phe276Cys (c.827T>G) is associated with DBT-related disorder, maple syrup urine disease, maple syrup urine disease type 1A (ClinVar).

How common is DBT p.Phe276Cys (c.827T>G) in the general population?

DBT p.Phe276Cys (c.827T>G) is ultra-rare (popmax 0.0257%, nfe) (gnomAD).

What do computational predictors say about DBT p.Phe276Cys (c.827T>G)?

AlphaMissense predicts likely pathogenic (score 0.8791) — an in-silico prediction, not a clinical call.

DBT p.Phe276Cys

c.827T>G · rs121964999 · VCV11943

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.8791 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0257%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DBT-related disorder

Computational evidence

Protein change
AlphaMissense	0.8791	likely pathogenic ✓ concordant with ClinVar
REVEL	0.842	moderately pathogenic-leaning
SaProt	LLR -14.25	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 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 54 kb · p 0.0036 · regional, not allelic
Overall
CADD	28.7	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 0.0257% European (non-Finnish) · 303/1,179,138 alleles

Filtering AF 0.0233% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0224%

Overall 0.02% 322/1,613,122 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0257%	3,892
Remaining individualsnot grpmax-eligible	0.016%	6,246
Finnishnot grpmax-eligible	0.0109%	9,149
African / African-American	0.00267%	37,468

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.Phe276Cys
Coding: c.827T>G
MANE Select: NM_001918
dbSNP: rs121964999
Type: single nucleotide variant
Location: chr1:100214929 (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 276: a UniProt-annotated variant site (in msud2)

Full DBT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DBT-related disorder

Also linked: maple syrup urine disease maple syrup urine disease type 1A maple syrup urine disease type 2

Similar variants

DBT p.Phe276fs Pathogenic/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 c.773-2A>G 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-phe276cys (accessed [today's date]).

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