# NM_001918.5(DBT):c.1126C>T (p.Arg376Cys)

https://sugi.bio/variant/dbt-p-arg376cys

## Summary

**DBT p.Arg376Cys (c.1126C>T)** is classified **Pathogenic/Likely pathogenic** in DBT (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-08-28). AlphaMissense: likely benign (0.2688); Very rare (popmax 0.00333%, amr); Associated with maple syrup urine disease type 2.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs768389398 · 6 submitters · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00333%, amr)

## For patients & families {#patients}

This is a change in the DBT gene that is considered likely disease-causing, submitted by 6 submitters, and is linked to maple syrup urine disease type 2.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |
| Diagnostic panels | DBT is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Maple syrup urine disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the pharynx — Very frequent (99-80%)
- Intellectual disability — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Reduced tendon reflexes — Very frequent (99-80%)
- Abnormality of the voice — Very frequent (99-80%)
- Respiratory insufficiency — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008596/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DBT](https://sugi.bio/atlas/gene/DBT/) |
| Protein change (HGVS p.) | p.Arg376Cys |
| Coding change (HGVS c.) | c.1126C>T |
| MANE Select transcript | [NM_001918](https://www.ncbi.nlm.nih.gov/nuccore/NM_001918) |
| dbSNP | [rs768389398](https://www.ncbi.nlm.nih.gov/snp/rs768389398/) |
| Variant type | single nucleotide variant |
| Location | chr1:100206528-100206528 (GRCh38) |
| ClinVar | [VCV554556](https://www.ncbi.nlm.nih.gov/clinvar/variation/554556/) |

**All HGVS expressions:** `NC_000001.10:g.100672084G>A`, `NC_000001.11:g.100206528G>A`, `NG_011852.2:g.48326C>T`, `NM_001918.5:c.1126C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.2688) — ⚠ discordant with the pathogenic call
- REVEL 0.742 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -14.768 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 11.717, GERP 1.81, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 32.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.88** across the covering region of the MANE Select transcript (100,196,258–100,249,820), spanning 53,562 bp. Chi-square p 0.0036. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00333%** (amr) · FAF95 0.000875% · FAF99 0.000443% · 2/59,988 in the highest group · 13/1,612,872 alleles overall — very rare (popmax 0.00333%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00333% | 29,994 |
| South Asian | 0.00329% | 30,353 |
| African / African-American | 0.00267% | 37,445 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,458 |
| European (non-Finnish) | 0.000424% | 235,795 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**DBT** population constraint: LOEUF 1.255, pLI 3.6458e-09, missense-Z 1.3238; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **maple syrup urine disease** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 78.71, 55% of residues very-high.

**5 experimental structure(s)** (PDB): [1K8M](https://www.rcsb.org/structure/1K8M), [1K8O](https://www.rcsb.org/structure/1K8O), [1ZWV](https://www.rcsb.org/structure/1ZWV), [2COO](https://www.rcsb.org/structure/2COO), [3RNM](https://www.rcsb.org/structure/3RNM).

## What this gene does {#gene-function}

*Describes the biological roles of DBT (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** DBT's established molecular role includes ubiquitin protein ligase binding. In Reactome, DBT is annotated in disease pathway(s) including **Branched-chain ketoacid dehydrogenase kinase deficiency**, **H139Hfs13* PPM1K causes a mild variant of  MSUD**.

**Disease mechanism (Reactome):** DBT loss or alteration is curated in [Branched-chain ketoacid dehydrogenase kinase deficiency](https://reactome.org/content/detail/R-HSA-9912481), [H139Hfs13* PPM1K causes a mild variant of  MSUD](https://reactome.org/content/detail/R-HSA-9912529), [Loss-of-function mutations in BCKDHA or BCKDHB cause MSUD](https://reactome.org/content/detail/R-HSA-9865125).

### Pathways affected {#pathways}

DBT participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Branched-chain ketoacid dehydrogenase kinase deficiency](https://reactome.org/content/detail/R-HSA-9912481) | curated |
| ⚕ [H139Hfs13* PPM1K causes a mild variant of  MSUD](https://reactome.org/content/detail/R-HSA-9912529) | curated |
| ⚕ [Loss-of-function mutations in BCKDHA or BCKDHB cause MSUD](https://reactome.org/content/detail/R-HSA-9865125) | curated |
| ⚕ [Loss-of-function mutations in DBT cause MSUD2](https://reactome.org/content/detail/R-HSA-9865113) | curated |
| ⚕ [Loss-of-function mutations in DLD cause MSUD3/DLDD](https://reactome.org/content/detail/R-HSA-9907570) | curated |
| [BCKDH synthesizes BCAA-CoA from KIC, KMVA, KIV](https://reactome.org/content/detail/R-HSA-9859138) | curated |
| [Branched-chain amino acid catabolism](https://reactome.org/content/detail/R-HSA-70895) | curated |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | curated |
| [Protein lipoylation](https://reactome.org/content/detail/R-HSA-9857492) | curated |
| [RHOH GTPase cycle](https://reactome.org/content/detail/R-HSA-9013407) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** ubiquitin protein ligase binding.

**Biological process:** branched-chain amino acid catabolic process, branched-chain alpha-keto acid decarboxylation to branched-chain acyl-CoA.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-28.

**Submitter consensus:** conflicting (4 Likely pathogenic, 1 Uncertain significance, 1 Pathogenic).

**Submission history:** 6 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome-Nilou Lab | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-11-07 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-16 |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2017-10-25 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-08-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-05-22 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2018-10-01 |

## Associated conditions {#conditions}

[maple syrup urine disease type 2](https://sugi.bio/atlas/disease/maple-syrup-urine-disease-type-2/), [maple syrup urine disease](https://sugi.bio/atlas/disease/maple-syrup-urine-disease/), [maple syrup urine disease type 1A](https://sugi.bio/atlas/disease/maple-syrup-urine-disease-type-1a/).

**Reported phenotype names (ClinVar):** Maple syrup urine disease type 2, Maple syrup urine disease, not provided, Maple syrup urine disease type 1A, Maple syrup urine disease, type II, none provided, MSUD type 1A.

## Similar variants {#similar}

Related DBT variant pages (same residue, condition, or type): [DBT p.Arg376His](/variant/dbt-p-arg376his), [DBT c.1018-550A>G](/variant/dbt-c-1018-minus-550a-g), [DBT c.1281+1G>A](/variant/dbt-c-1281-plus-1g-a), [DBT c.1281+1G>T](/variant/dbt-c-1281-plus-1g-t), [DBT c.51+1G>T](/variant/dbt-c-51-plus-1g-t), [DBT c.52-1G>A](/variant/dbt-c-52-minus-1g-a), [DBT c.773-2A>G](/variant/dbt-c-773-minus-2a-g), [DBT p.Arg169Ter](/variant/dbt-p-arg169ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 554556). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*