# NM_018706.7(DHTKD1):c.1544del (p.Pro515fs)

https://sugi.bio/variant/dhtkd1-p-pro515fs

## Summary

**DHTKD1 p.Pro515fs (c.1544del)** is classified **Pathogenic** in DHTKD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-29). No gnomAD frequency available for this variant; Associated with 2-aminoadipic 2-oxoadipic aciduria.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2491491847 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DHTKD1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to 2-aminoadipic 2-oxoadipic aciduria.

*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, Infancy |
| Diagnostic panels | DHTKD1 is a diagnostic-grade gene on 9 Genomics England panels |

**Commonly reported features of 2-aminoadipic 2-oxoadipic aciduria** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Alpha-aminoadipic aciduria — Very frequent (99-80%)
- 2-hydroxyadipic aciduria — Frequent (79-30%)
- Elevated circulating 2-aminoadipic acid concentration — Frequent (79-30%)
- Microcephaly — Occasional (29-5%)
- Autism — Occasional (29-5%)
- Delayed speech and language development — Occasional (29-5%)
- Intellectual disability — Occasional (29-5%)
- Seizure — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016708/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DHTKD1](https://sugi.bio/atlas/gene/DHTKD1/) |
| Protein change (HGVS p.) | p.Pro515fs |
| Coding change (HGVS c.) | c.1544del |
| MANE Select transcript | [NM_018706](https://www.ncbi.nlm.nih.gov/nuccore/NM_018706) |
| dbSNP | [rs2491491847](https://www.ncbi.nlm.nih.gov/snp/rs2491491847/) |
| Variant type | Deletion |
| Location | chr10:12097868-12097868 (GRCh38) |
| ClinVar | [VCV2030322](https://www.ncbi.nlm.nih.gov/clinvar/variation/2030322/) |

**All HGVS expressions:** `NC_000010.10:g.12139868del`, `NC_000010.11:g.12097869del`, `NG_033248.1:g.33953del`, `NG_033248.2:g.33917del`, `NM_018706.7:c.1544del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 5.011, GERP 2.02, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.864, pLI 2.3646e-15. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 17**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**DHTKD1** population constraint: LOEUF 0.864, pLI 2.3646e-15, missense-Z 0.030914. *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):

- **2-aminoadipic 2-oxoadipic aciduria** — Definitive (AR)

## Protein context {#protein}

Residue **515** lies in a UniProt-annotated variant site (in aakad); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 95.19, 92% of residues very-high.

**8 experimental structure(s)** (PDB): [5RVW](https://www.rcsb.org/structure/5RVW), [5RVX](https://www.rcsb.org/structure/5RVX), [5RVY](https://www.rcsb.org/structure/5RVY), [5RVZ](https://www.rcsb.org/structure/5RVZ), [5RW0](https://www.rcsb.org/structure/5RW0), [5RW1](https://www.rcsb.org/structure/5RW1).

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

*Describes the biological roles of DHTKD1 (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:** DHTKD1's established molecular role includes 2-oxoadipate dehydrogenase activity.


### Pathways affected {#pathways}

DHTKD1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [OADH complex synthesizes glutaryl-CoA from 2-OA](https://reactome.org/content/detail/R-HSA-9858328) | curated |

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

**Molecular function:** 2-oxoadipate dehydrogenase activity.

**Biological process:** generation of precursor metabolites and energy.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-29.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-29 |

## Associated conditions {#conditions}

[2-aminoadipic 2-oxoadipic aciduria](https://sugi.bio/atlas/disease/2-aminoadipic-2-oxoadipic-aciduria/).

**Reported phenotype names (ClinVar):** 2-aminoadipic 2-oxoadipic aciduria, Aminoadipic aciduria, ALPHA-AMINOADIPIC AND ALPHA-KETOADIPIC ACIDURIA.

## Same-residue context {#hotspot}

Residue **515** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DHTKD1 p.Pro515Thr](/variant/dhtkd1-p-pro515thr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DHTKD1 variant pages (same residue, condition, or type): [DHTKD1 p.Pro515Ser](/variant/dhtkd1-p-pro515ser), [DHTKD1 p.Glu250fs](/variant/dhtkd1-p-glu250fs), [DHTKD1 p.Gly470fs](/variant/dhtkd1-p-gly470fs), [DHTKD1 c.1742_1756+29del](/variant/dhtkd1-c-1742-1756-plus-29del), [DHTKD1 c.2048-8_2050del](/variant/dhtkd1-c-2048-minus-8-2050del), [DHTKD1 p.Ala783fs](/variant/dhtkd1-p-ala783fs), [DHTKD1 p.Glu111fs](/variant/dhtkd1-p-glu111fs), [DHTKD1 p.Gly785fs](/variant/dhtkd1-p-gly785fs).

### 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 2030322). 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.*