# NM_005881.4(BCKDK):c.373G>A (p.Val125Met)

https://sugi.bio/variant/bckdk-p-val125met

## Summary

**BCKDK p.Val125Met (c.373G>A)** is classified **Uncertain significance** in BCKDK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-21). AlphaMissense: likely pathogenic (0.9608); Ultra-rare (popmax 0.0132%, nfe); Associated with branched-chain keto acid dehydrogenase kinase deficiency.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs141282419 · 3 submitters · 1 linked condition · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0132%, nfe)

## For patients & families {#patients}

This is a change in the BCKDK gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to branched-chain keto acid dehydrogenase kinase deficiency.

*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 |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | BCKDK is a diagnostic-grade gene on 7 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017389/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BCKDK](https://sugi.bio/atlas/gene/BCKDK/) |
| Protein change (HGVS p.) | p.Val125Met |
| Coding change (HGVS c.) | c.373G>A |
| MANE Select transcript | [NM_005881](https://www.ncbi.nlm.nih.gov/nuccore/NM_005881) |
| dbSNP | [rs141282419](https://www.ncbi.nlm.nih.gov/snp/rs141282419/) |
| Variant type | single nucleotide variant |
| Location | chr16:31109781-31109781 (GRCh38) |
| ClinVar | [VCV197262](https://www.ncbi.nlm.nih.gov/clinvar/variation/197262/) |

**All HGVS expressions:** `NC_000016.10:g.31109781G>A`, `NC_000016.9:g.31121102G>A`, `NG_033011.1:g.6488G>A`, `NM_001122957.4:c.373G>A`, `NM_001271926.3:c.373G>A`, `NM_005881.4:c.373G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9608)
- REVEL 0.407 (indeterminate)
- SaProt LLR -12.244 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- SpliceAI predicts **donor loss** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.807, GERP 2.18, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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 0.83** across the covering region of the MANE Select transcript (31,109,224–31,112,262), spanning 3,038 bp. Chi-square p 4.5e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.22**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 7 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  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.*
- Population frequency (gnomAD v4.1): grpmax **0.0132%** (nfe) · FAF95 0.0115% · FAF99 0.0108% · 156/1,179,910 in the highest group · 161/1,613,498 alleles overall — ultra-rare (popmax 0.0132%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0132% | 7,564 |
| East Asian | 0.00445% | 22,447 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,238 |
| Finnish (not grpmax-eligible) | 0.00157% | 63,612 |

*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}

**BCKDK** population constraint: LOEUF 0.855, pLI 3.1983e-06, missense-Z 1.7423. *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):

- **branched-chain keto acid dehydrogenase kinase deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **125** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 84.03, 68% of residues very-high.

**5 experimental structure(s)** (PDB): [7ZPE](https://www.rcsb.org/structure/7ZPE), [8F5F](https://www.rcsb.org/structure/8F5F), [8F5J](https://www.rcsb.org/structure/8F5J), [8F5S](https://www.rcsb.org/structure/8F5S), [9DI9](https://www.rcsb.org/structure/9DI9).

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

*Describes the biological roles of BCKDK (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:** BCKDK's established molecular role includes protein serine/threonine phosphatase activity. In Reactome, BCKDK is annotated in disease pathway(s) including **Branched-chain ketoacid dehydrogenase kinase deficiency**.

**Disease mechanism (Reactome):** BCKDK loss or alteration is curated in [Branched-chain ketoacid dehydrogenase kinase deficiency](https://reactome.org/content/detail/R-HSA-9912481).

### Pathways affected {#pathways}

BCKDK participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Branched-chain ketoacid dehydrogenase kinase deficiency](https://reactome.org/content/detail/R-HSA-9912481) | curated |
| [Branched-chain amino acid catabolism](https://reactome.org/content/detail/R-HSA-70895) | curated |

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

**Molecular function:** protein serine/threonine phosphatase activity.

**Biological process:** lipid biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-21.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2014–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-01-22 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2014-12-17 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-21 |

## Associated conditions {#conditions}

[branched-chain keto acid dehydrogenase kinase deficiency](https://sugi.bio/atlas/disease/branched-chain-keto-acid-dehydrogenase-kinase-deficiency/).

**Reported phenotype names (ClinVar):** Branched-chain keto acid dehydrogenase kinase deficiency, not provided, none provided, BCKDK DEFICIENCY.

## Similar variants {#similar}

Related BCKDK variant pages (same residue, condition, or type): [BCKDK p.Arg156Ter](/variant/bckdk-p-arg156ter), [BCKDK c.846-3T>A](/variant/bckdk-c-846-minus-3t-a), [BCKDK p.Ala283Thr](/variant/bckdk-p-ala283thr), [BCKDK p.Ala29Val](/variant/bckdk-p-ala29val), [BCKDK p.Arg177Trp](/variant/bckdk-p-arg177trp), [BCKDK p.Ile102Thr](/variant/bckdk-p-ile102thr), [BCKDK p.Ile122Val](/variant/bckdk-p-ile122val), [BCKDK p.Ile230Met](/variant/bckdk-p-ile230met).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 197262). 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.*