# NM_018706.7(DHTKD1):c.2396_2397del (p.Pro799fs)

https://sugi.bio/variant/dhtkd1-p-pro799fs

## Summary

**DHTKD1 p.Pro799fs (c.2396_2397del)** is classified **Likely pathogenic** in DHTKD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-30). Ultra-rare (popmax 0.0167%, mid); Associated with DHTKD1-related disorder.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs757583515 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0167%, mid)

## For patients & families {#patients}

This is a change in the DHTKD1 gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to DHTKD1-related disorder.

*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 | [DHTKD1](https://sugi.bio/atlas/gene/DHTKD1/) |
| Protein change (HGVS p.) | p.Pro799fs |
| Coding change (HGVS c.) | c.2396_2397del |
| MANE Select transcript | [NM_018706](https://www.ncbi.nlm.nih.gov/nuccore/NM_018706) |
| dbSNP | [rs757583515](https://www.ncbi.nlm.nih.gov/snp/rs757583515/) |
| Variant type | Deletion |
| Location | chr10:12117749-12117750 (GRCh38) |
| ClinVar | [VCV1324228](https://www.ncbi.nlm.nih.gov/clinvar/variation/1324228/) |

**All HGVS expressions:** `NC_000010.10:g.12159748_12159749del`, `NC_000010.11:g.12117749_12117750del`, `NG_033248.1:g.53833_53834del`, `NM_018706.6:c.2396_2397delCA`, `NM_018706.7:c.2396_2397del`

## 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 5.881, GERP 1.76, 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 14 of 17**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 35.0**. 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: **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 (gnomAD v4.1): grpmax **0.0167%** (mid) · FAF95 0.00453% · FAF99 0.00324% · 1/5,986 in the highest group · 11/1,580,076 alleles overall — ultra-rare (popmax 0.0167%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0167% | 5,986 |
| South Asian | 0.00916% | 10,914 |
| Remaining individuals (not grpmax-eligible) | 0.00327% | 30,626 |

*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 **799** 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}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-05-30.

**Submitter consensus:** unanimous (2/2 Likely pathogenic).

**Submission history:** 2 submissions (2020–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-05-30 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-03-25 |

## Associated conditions {#conditions}

[DHTKD1-related disorder](https://sugi.bio/atlas/disease/dhtkd1-related-disorder/).

**Reported phenotype names (ClinVar):** DHTKD1-related disorder, not provided, DHTKD1-related condition, none provided.

## Similar variants {#similar}

Related DHTKD1 variant pages (same residue, condition, or type): [DHTKD1 p.Val423fs](/variant/dhtkd1-p-val423fs), [DHTKD1 c.2572+1G>A](/variant/dhtkd1-c-2572-plus-1g-a), [DHTKD1 p.Arg410Ter](/variant/dhtkd1-p-arg410ter), [DHTKD1 p.Arg712Ter](/variant/dhtkd1-p-arg712ter), [DHTKD1 p.Trp687Ter](/variant/dhtkd1-p-trp687ter), [DHTKD1 p.Tyr853Ter](/variant/dhtkd1-p-tyr853ter), [DHTKD1 p.Gln510Ter](/variant/dhtkd1-p-gln510ter), [DHTKD1 p.Gly729Arg](/variant/dhtkd1-p-gly729arg).

### 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 1324228). 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.*