# NM_018706.7(DHTKD1):c.2184C>T (p.Asp728=)

https://sugi.bio/variant/dhtkd1-p-asp728

## Summary

**DHTKD1 p.Asp728= (c.2184C>T)** is classified **Benign/Likely benign** in DHTKD1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-05-04). Rare (popmax 0.396%, afr); Associated with 2-aminoadipic 2-oxoadipic aciduria.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs142017323 · 6 submitters · 1 linked condition · rare (popmax 0.396%, afr)

## For patients & families {#patients}

This is a change in the DHTKD1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 6 submitters, 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.Asp728= |
| Coding change (HGVS c.) | c.2184C>T |
| MANE Select transcript | [NM_018706](https://www.ncbi.nlm.nih.gov/nuccore/NM_018706) |
| dbSNP | [rs142017323](https://www.ncbi.nlm.nih.gov/snp/rs142017323/) |
| Variant type | single nucleotide variant |
| Location | chr10:12112929-12112929 (GRCh38) |
| ClinVar | [VCV733551](https://www.ncbi.nlm.nih.gov/clinvar/variation/733551/) |

**All HGVS expressions:** `NC_000010.10:g.12154928C>T`, `NC_000010.11:g.12112929C>T`, `NG_033248.1:g.49013C>T`, `NM_018706.7:c.2184C>T`

## Computational & population evidence {#evidence}

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

- **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 -6.228, GERP -3.5 — fast-evolving / accelerated position
- CADD: **PHRED 0.78**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.32 acceptor loss), 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 **0.396%** (afr) · FAF95 0.359% · FAF99 0.345% · 297/74,940 in the highest group · 474/1,611,274 alleles overall — rare (popmax 0.396%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.396% | 252 |
| Admixed American | 0.0622% | 1,607 |
| Remaining individuals (not grpmax-eligible) | 0.0449% | 2,228 |
| Middle Eastern | 0.033% | 3,028 |
| European (non-Finnish) | 0.00865% | 11,557 |
| South Asian | 0.00662% | 15,096 |
| East Asian | 0.00448% | 22,314 |

*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 **728** lies in a UniProt-annotated variant site (in aakad).

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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-05-04.

**Submitter consensus:** conflicting (5 Likely benign, 1 Benign).

**Submission history:** 6 submissions (2019–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely benign | criteria provided, single submitter | clinical testing | 2019-12-18 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-08-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-08-11 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-05-04 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-12-27 |

## 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, not provided, DHTKD1-related disorder, not specified, AllHighlyPenetrant, none provided, ALPHA-AMINOADIPIC AND ALPHA-KETOADIPIC ACIDURIA, Aminoadipic aciduria, DHTKD1-related condition.

## Similar variants {#similar}

Related DHTKD1 variant pages (same residue, condition, or type): [DHTKD1 c.1671+1G>A](/variant/dhtkd1-c-1671-plus-1g-a), [DHTKD1 c.1897-1G>A](/variant/dhtkd1-c-1897-minus-1g-a), [DHTKD1 c.2320-2A>T](/variant/dhtkd1-c-2320-minus-2a-t), [DHTKD1 c.2572+1G>A](/variant/dhtkd1-c-2572-plus-1g-a), [DHTKD1 p.Arg163Ter](/variant/dhtkd1-p-arg163ter), [DHTKD1 p.Arg410Ter](/variant/dhtkd1-p-arg410ter), [DHTKD1 p.Arg455Ter](/variant/dhtkd1-p-arg455ter), [DHTKD1 p.Arg712Ter](/variant/dhtkd1-p-arg712ter).

### 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 733551). 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.*