# NM_000108.5(DLD):c.226C>T (p.Leu76Phe)

https://sugi.bio/variant/dld-p-leu76phe

## Summary

**DLD p.Leu76Phe (c.226C>T)** is classified **Uncertain significance** in DLD (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely pathogenic (0.6243); Very rare (popmax 0.00687%, nfe); Associated with pyruvate dehydrogenase deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs967089304 · 1 submitter · 3 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00687%, nfe)

## For patients & families {#patients}

This is a change in the DLD gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Leu76Phe |
| Coding change (HGVS c.) | c.226C>T |
| MANE Select transcript | [NM_000108](https://www.ncbi.nlm.nih.gov/nuccore/NM_000108) |
| dbSNP | [rs967089304](https://www.ncbi.nlm.nih.gov/snp/rs967089304/) |
| Variant type | single nucleotide variant |
| Location | chr7:107902352-107902352 (GRCh38) |
| ClinVar | [VCV909237](https://www.ncbi.nlm.nih.gov/clinvar/variation/909237/) |

**All HGVS expressions:** `NC_000007.13:g.107542797C>T`, `NC_000007.14:g.107902352C>T`, `NG_008045.1:g.16212C>T`, `NM_000108.5:c.226C>T`, `NM_001289750.1:c.-30-1126C>T`, `NM_001289751.1:c.198+535C>T`, `NM_001289752.1:c.226C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6243)
- REVEL 0.358 (indeterminate)
- SaProt LLR -7.756 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 5.949, GERP 1.2, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 23.8**. 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 0.89** across the covering region of the MANE Select transcript (107,891,251–107,919,256), spanning 28,005 bp. Chi-square p 0.0061. 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 **0.00687%** (nfe) · FAF95 0.00563% · FAF99 0.00515% · 81/1,179,852 in the highest group · 84/1,613,684 alleles overall — very rare (popmax 0.00687%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00687% | 14,566 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,235 |
| Admixed American | 0.00167% | 59,990 |

*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 **76** lies in a binding site; a β-strand.

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-01-12.

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

**Submission history:** 3 submissions (2018); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |

## 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, Pyruvate dehydrogenase E3 deficiency, Leigh syndrome, PYRUVATE DECARBOXYLASE DEFICIENCY, Pyruvate Dehydrogenase Complex Deficiency Disease, Pyruvate dehydrogenase deficiency, Ataxia with lactic acidosis 1, PDH DEFICIENCY, Leigh's syndrome, Leigh Disease.

## Same-residue context {#hotspot}

Residue **76** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DLD p.Leu76fs](/variant/dld-p-leu76fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DLD variant pages (same residue, condition, or type): [DLD p.Leu76=](/variant/dld-p-leu76), [DLD p.Leu76fs](/variant/dld-p-leu76fs), [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).

### 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 909237). 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.*