# NM_000108.5(DLD):c.249T>C (p.Val83=)

https://sugi.bio/variant/dld-p-val83

## Summary

**DLD p.Val83= (c.249T>C)** is classified **Benign** in DLD (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-02). Low-frequency (popmax 3.14%, afr); Associated with pyruvate dehydrogenase deficiency.

**At a glance:** Benign · review: Multiple submitters · rsID rs2228664 · 7 submitters · 3 linked conditions · low-frequency (popmax 3.14%, afr)

## For patients & families {#patients}

This is a change in the DLD gene that is classified as benign — not considered disease-causing, submitted by 7 submitters, and is linked to pyruvate dehydrogenase 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, Not applicable, X-linked dominant |
| Age of onset (of this condition) | Childhood, Infancy, Neonatal |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DLD is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of Pyruvate dehydrogenase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypotonia — Very frequent (99-80%)
- Lethargy — Very frequent (99-80%)
- Growth delay — Very frequent (99-80%)
- Abnormal facial shape — Very frequent (99-80%)
- Feeding difficulties in infancy — Very frequent (99-80%)
- Microcephaly — Frequent (79-30%)
- Abnormality of eye movement — Frequent (79-30%)
- Seizure — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007513/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DLD](https://sugi.bio/atlas/gene/DLD/) |
| Protein change (HGVS p.) | p.Val83= |
| Coding change (HGVS c.) | c.249T>C |
| MANE Select transcript | [NM_000108](https://www.ncbi.nlm.nih.gov/nuccore/NM_000108) |
| dbSNP | [rs2228664](https://www.ncbi.nlm.nih.gov/snp/rs2228664/) |
| Variant type | single nucleotide variant |
| Location | chr7:107902375-107902375 (GRCh38) |
| ClinVar | [VCV137092](https://www.ncbi.nlm.nih.gov/clinvar/variation/137092/) |

**All HGVS expressions:** `NC_000007.13:g.107542820T>C`, `NC_000007.14:g.107902375T>C`, `NG_008045.1:g.16235T>C`, `NM_000108.5:c.249T>C`, `NM_001289750.1:c.-30-1103T>C`, `NM_001289751.1:c.198+558T>C`, `NM_001289752.1:c.249T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 (below), not from a missing predictor score.
- Conservation: phyloP 1.321, GERP -1.92, phastCons 1 — weakly conserved position
- CADD: **PHRED 9.617**. 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: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.36 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **3.14%** (afr) · FAF95 3.03% · FAF99 2.99% · 2,355/75,024 in the highest group · 2,643/1,613,914 alleles overall — low-frequency (popmax 3.14%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 3.14% | 32 |
| Admixed American | 0.198% | 504 |
| Remaining individuals (not grpmax-eligible) | 0.181% | 553 |
| Middle Eastern | 0.149% | 673 |
| South Asian | 0.00659% | 15,179 |
| European (non-Finnish) | 0.00339% | 29,497 |
| East Asian | 0.00223% | 44,808 |

*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}

**DLD** population constraint: LOEUF 0.727, pLI 0.00025663, missense-Z 1.5317. *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):

- **Leigh syndrome** — Definitive (AR)
- **pyruvate dehydrogenase E3 deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **83** lies in a disulfide bond; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 93.69, 92% of residues very-high.

**17 experimental structure(s)** (PDB): [1ZMC](https://www.rcsb.org/structure/1ZMC), [1ZMD](https://www.rcsb.org/structure/1ZMD), [1ZY8](https://www.rcsb.org/structure/1ZY8), [2F5Z](https://www.rcsb.org/structure/2F5Z), [3RNM](https://www.rcsb.org/structure/3RNM), [5J5Z](https://www.rcsb.org/structure/5J5Z) — incl. mutant structure 5J5Z.

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

*Describes the biological roles of DLD (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:** DLD's established molecular role includes dihydrolipoyl dehydrogenase (NADH) activity. In Reactome, DLD is annotated in disease pathway(s) including **Branched-chain ketoacid dehydrogenase kinase deficiency**, **H139Hfs13* PPM1K causes a mild variant of  MSUD**.

**Disease mechanism (Reactome):** DLD 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 DBT cause MSUD2](https://reactome.org/content/detail/R-HSA-9865113).

### Pathways affected {#pathways}

DLD participates in **13 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 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 |
| [Glycine degradation](https://reactome.org/content/detail/R-HSA-6783984) | curated |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | curated |
| [OADH complex synthesizes glutaryl-CoA from 2-OA](https://reactome.org/content/detail/R-HSA-9858328) | curated |
| [OGDH complex synthesizes succinyl-CoA from 2-OG](https://reactome.org/content/detail/R-HSA-9853506) | curated |
| [PDH complex synthesizes acetyl-CoA from PYR](https://reactome.org/content/detail/R-HSA-9861559) | curated |
| [Regulation of pyruvate dehydrogenase (PDH) complex](https://reactome.org/content/detail/R-HSA-204174) | curated |
| [Signaling by Retinoic Acid](https://reactome.org/content/detail/R-HSA-5362517) | curated |

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

**Molecular function:** dihydrolipoyl dehydrogenase (NADH) activity.

**Biological process:** pyruvate decarboxylation to acetyl-CoA, branched-chain amino acid catabolic process, obsolete L-lysine catabolic process to acetyl-CoA, 2-oxoglutarate decarboxylation to succinyl-CoA, branched-chain alpha-keto acid decarboxylation to branched-chain acyl-CoA.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-02.

**Submitter consensus:** conflicting (8 Benign, 1 Likely benign).

**Submission history:** 9 submissions (2012–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-02 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2019-04-05 |
| Natera, Inc. | Benign | no assertion criteria provided | clinical testing | 2020-09-16 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2012-12-20 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | no assertion criteria provided | clinical testing | 2016-03-16 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |

## Associated conditions {#conditions}

[pyruvate dehydrogenase deficiency](https://sugi.bio/atlas/disease/pyruvate-dehydrogenase-deficiency/), [pyruvate dehydrogenase E3 deficiency](https://sugi.bio/atlas/disease/pyruvate-dehydrogenase-e3-deficiency/), [Leigh syndrome](https://sugi.bio/atlas/disease/leigh-syndrome/).

**Reported phenotype names (ClinVar):** Pyruvate dehydrogenase complex deficiency, not specified, Leigh syndrome, not provided, Pyruvate dehydrogenase E3 deficiency, AllHighlyPenetrant, none provided, PYRUVATE DECARBOXYLASE DEFICIENCY, Pyruvate Dehydrogenase Complex Deficiency Disease, Pyruvate dehydrogenase deficiency.

## Similar variants {#similar}

Related DLD variant pages (same residue, condition, or type): [DLD c.1464+1G>A](/variant/dld-c-1464-plus-1g-a), [DLD c.198+1G>T](/variant/dld-c-198-plus-1g-t), [DLD c.39+1G>A](/variant/dld-c-39-plus-1g-a), [DLD c.40-2A>G](/variant/dld-c-40-minus-2a-g), [DLD c.583-1G>C](/variant/dld-c-583-minus-1g-c), [DLD c.684+1G>T](/variant/dld-c-684-plus-1g-t), [DLD c.875+1G>A](/variant/dld-c-875-plus-1g-a), [DLD p.Arg315Ter](/variant/dld-p-arg315ter).

### 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 137092). 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.*