# NM_001931.5(DLAT):c.1202C>T (p.Pro401Leu)

https://sugi.bio/variant/dlat-p-pro401leu

## Summary

**DLAT p.Pro401Leu (c.1202C>T)** is classified **Uncertain significance** in DLAT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-28). AlphaMissense: likely benign (0.0714); Very rare (popmax 0.00988%, sas); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs781794850 · 3 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00988%, sas)

## For patients & families {#patients}

This is a change in the DLAT gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to Inborn genetic diseases.

*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 | [DLAT](https://sugi.bio/atlas/gene/DLAT/) |
| Protein change (HGVS p.) | p.Pro401Leu |
| Coding change (HGVS c.) | c.1202C>T |
| MANE Select transcript | [NM_001931](https://www.ncbi.nlm.nih.gov/nuccore/NM_001931) |
| dbSNP | [rs781794850](https://www.ncbi.nlm.nih.gov/snp/rs781794850/) |
| Variant type | single nucleotide variant |
| Location | chr11:112045142-112045142 (GRCh38) |
| ClinVar | [VCV547881](https://www.ncbi.nlm.nih.gov/clinvar/variation/547881/) |

**All HGVS expressions:** `NC_000011.10:g.112045142C>T`, `NC_000011.9:g.111915866C>T`, `NG_013342.1:g.25329C>T`, `NM_001372031.1:c.1202C>T`, `NM_001372032.1:c.1196C>T`, `NM_001372033.1:c.1202C>T`, `NM_001372034.1:c.1169C>T`, `NM_001372035.1:c.1202C>T`, `NM_001372036.1:c.1076C>T`, `NM_001372037.1:c.1034C>T`, `NM_001372038.1:c.923C>T`, `NM_001372039.1:c.887C>T`, `NM_001372040.1:c.821C>T`, `NM_001372041.1:c.887C>T`, `NM_001372042.1:c.740C>T`, `NM_001931.5:c.1202C>T`, `NR_164072.1:n.1079C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0714)
- REVEL 0.067 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -10.198 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- Conservation: phyloP 4.901, GERP 1.49, phastCons 0.916 — highly conserved (differs from AlphaMissense)
- 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 0.91** across the covering region of the MANE Select transcript (112,025,473–112,062,532), spanning 37,059 bp. Chi-square p 0.014. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.33 acceptor gain), 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 **0.00988%** (sas) · FAF95 0.00514% · FAF99 0.00375% · 9/91,080 in the highest group · 39/1,613,738 alleles overall — very rare (popmax 0.00988%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00988% | 10,120 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,821 |
| African / African-American | 0.00267% | 37,442 |
| European (non-Finnish) | 0.00203% | 49,161 |
| 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}

**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}


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.


### 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-28.

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

**Submission history:** 3 submissions (2016–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-11-07 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-10-03 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [pyruvate dehydrogenase E2 deficiency](https://sugi.bio/atlas/disease/pyruvate-dehydrogenase-e2-deficiency/).

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

## Similar variants {#similar}

Related DLAT variant pages (same residue, condition, or type): [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), [DLAT p.Ala191Val](/variant/dlat-p-ala191val).

### 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 547881). 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.*