# NM_001931.5(DLAT):c.975G>A (p.Pro325=)

https://sugi.bio/variant/dlat-p-pro325

## Summary

**DLAT p.Pro325= (c.975G>A)** is classified **Likely pathogenic** in DLAT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-14). Very rare (popmax 0.000932%, nfe); Associated with pyruvate dehydrogenase E2 deficiency.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1432866316 · 1 submitter · 1 linked condition · very rare (popmax 0.000932%, nfe)

## For patients & families {#patients}

This is a change in the DLAT gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to pyruvate dehydrogenase E2 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 | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DLAT is a diagnostic-grade gene on 10 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/0016712/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DLAT](https://sugi.bio/atlas/gene/DLAT/) |
| Protein change (HGVS p.) | p.Pro325= |
| Coding change (HGVS c.) | c.975G>A |
| MANE Select transcript | [NM_001931](https://www.ncbi.nlm.nih.gov/nuccore/NM_001931) |
| dbSNP | [rs1432866316](https://www.ncbi.nlm.nih.gov/snp/rs1432866316/) |
| Variant type | single nucleotide variant |
| Location | chr11:112037460-112037460 (GRCh38) |
| ClinVar | [VCV1252016](https://www.ncbi.nlm.nih.gov/clinvar/variation/1252016/) |

**All HGVS expressions:** `NC_000011.10:g.112037460G>A`, `NC_000011.9:g.111908184G>A`, `NG_013342.1:g.17647G>A`, `NM_001372031.1:c.975G>A`, `NM_001372032.1:c.975G>A`, `NM_001372033.1:c.975G>A`, `NM_001372034.1:c.942G>A`, `NM_001372035.1:c.975G>A`, `NM_001372036.1:c.849G>A`, `NM_001372037.1:c.807G>A`, `NM_001372038.1:c.696G>A`, `NM_001372039.1:c.661-1784G>A`, `NM_001372040.1:c.594G>A`, `NM_001372041.1:c.661-1784G>A`, `NM_001372042.1:c.513G>A`, `NM_001931.5:c.975G>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 gain** (Δ 0.51) — consistent with the pathogenic call
- Conservation: phyloP 5.873, GERP -0.587, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 23.2**. 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 **0.23**, acceptor gain **0.00**, donor gain **0.51**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.23**, acceptor gain **0.00**, donor gain **0.51**.
- Pangolin: Δ**0.77** (gain), gain 0.77 / loss 0.59. 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 **0.000932%** (nfe) · FAF95 0.0005% · FAF99 0.000366% · 11/1,179,952 in the highest group · 11/1,613,874 alleles overall — very rare (popmax 0.000932%, nfe).

*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}

**DLAT** population constraint: LOEUF 0.759, pLI 3.1812e-06, missense-Z 1.3325. *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** — Moderate (AR)

## Protein context {#protein}

Residue **325** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 72.59, 27% of residues very-high.

**13 experimental structure(s)** (PDB): [1FYC](https://www.rcsb.org/structure/1FYC), [1Y8N](https://www.rcsb.org/structure/1Y8N), [1Y8O](https://www.rcsb.org/structure/1Y8O), [1Y8P](https://www.rcsb.org/structure/1Y8P), [2DNE](https://www.rcsb.org/structure/2DNE), [2PNR](https://www.rcsb.org/structure/2PNR).

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

*Describes the biological roles of DLAT (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:** DLAT's established molecular role includes dihydrolipoyllysine-residue acetyltransferase activity. p.Pro325= falls in the disordered region.


### Pathways affected {#pathways}

DLAT participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [PDH complex synthesizes acetyl-CoA from PYR](https://reactome.org/content/detail/R-HSA-9861559) | curated |
| [Protein lipoylation](https://reactome.org/content/detail/R-HSA-9857492) | 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:** dihydrolipoyllysine-residue acetyltransferase activity, identical protein binding.

**Biological process:** pyruvate decarboxylation to acetyl-CoA.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-14.

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

**Submission history:** 2 submissions (2021–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Pathogenic | flagged submission | research | 2021-04-29 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-14 |

## Associated conditions {#conditions}

[pyruvate dehydrogenase E2 deficiency](https://sugi.bio/atlas/disease/pyruvate-dehydrogenase-e2-deficiency/).

**Reported phenotype names (ClinVar):** Pyruvate dehydrogenase E2 deficiency, Dihydrolipoamide Acetyltransferase (E2) Deficiency, LACTIC ACIDEMIA DUE TO DEFECT OF E2 LIPOYL TRANSACETYLASE OF THE PYRUVATE DEHYDROGENASE COMPLEX.

## Similar variants {#similar}

Related DLAT variant pages (same residue, condition, or type): [DLAT p.Pro325Leu](/variant/dlat-p-pro325leu), [DLAT c.976-1G>A](/variant/dlat-c-976-minus-1g-a), [DLAT p.Arg435Ter](/variant/dlat-p-arg435ter), [DLAT p.Glu138Ter](/variant/dlat-p-glu138ter), [DLAT p.Val157Gly](/variant/dlat-p-val157gly), [DLAT c.1130-6T>G](/variant/dlat-c-1130-minus-6t-g), [DLAT p.Ala109Thr](/variant/dlat-p-ala109thr), [DLAT p.Ala191Gly](/variant/dlat-p-ala191gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 1252016). 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.*