# NM_001918.5(DBT):c.1017G>A (p.Lys339=)

https://sugi.bio/variant/dbt-p-lys339

## Summary

**DBT p.Lys339= (c.1017G>A)** is classified **Pathogenic/Likely pathogenic** in DBT (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-06-11). Very rare (popmax 0.00223%, eas); Associated with DBT-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1490661508 · 6 submitters · 4 linked conditions · very rare (popmax 0.00223%, eas)

## 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 DBT-related disorder.

*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.*

**Support & next steps:** [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.Lys339= |
| Coding change (HGVS c.) | c.1017G>A |
| MANE Select transcript | [NM_001918](https://www.ncbi.nlm.nih.gov/nuccore/NM_001918) |
| dbSNP | [rs1490661508](https://www.ncbi.nlm.nih.gov/snp/rs1490661508/) |
| Variant type | single nucleotide variant |
| Location | chr1:100210694-100210694 (GRCh38) |
| ClinVar | [VCV550402](https://www.ncbi.nlm.nih.gov/clinvar/variation/550402/) |

**All HGVS expressions:** `NC_000001.10:g.100676250C>T`, `NC_000001.11:g.100210694C>T`, `NG_011852.2:g.44160G>A`, `NM_001918.2:c.1017G>A`, `NM_001918.4:c.1017G>A`, `NM_001918.5:c.1017G>A`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.93) — consistent with the pathogenic call
- Conservation: phyloP 5.894, GERP 1.95, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 22.0**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.93**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.01**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.82** (loss), gain 0.11 / loss 0.82. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 7.9e-05% · FAF99 5.4e-05% · 1/44,808 in the highest group · 5/1,612,978 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,808 |
| European (non-Finnish) | 0.000339% | 294,816 |

*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 2026-06-11.

**Submitter consensus:** conflicting (3 Likely pathogenic, 2 Pathogenic, 1 Uncertain significance).

**Submission history:** 6 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2017-01-24 |
| Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-09-19 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-04-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-14 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2026-06-11 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-08-03 |

## Associated conditions {#conditions}

[DBT-related disorder](https://sugi.bio/atlas/disease/dbt-related-disorder/), [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/), [maple syrup urine disease type 2](https://sugi.bio/atlas/disease/maple-syrup-urine-disease-type-2/).

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

## Similar variants {#similar}

Related DBT variant pages (same residue, condition, or type): [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), [DBT p.Arg291Ter](/variant/dbt-p-arg291ter).

### 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 550402). 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.*