# NM_018706.7(DHTKD1):c.987G>C (p.Gln329His)

https://sugi.bio/variant/dhtkd1-p-gln329his

## Summary

**DHTKD1 p.Gln329His (c.987G>C)** is classified **Uncertain significance** in DHTKD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-23). AlphaMissense: likely pathogenic (0.801); Very rare (popmax 0.00134%, afr); Associated with 2-aminoadipic 2-oxoadipic aciduria.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1363866819 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00134%, afr)

## For patients & families {#patients}

This is a change in the DHTKD1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Gln329His |
| Coding change (HGVS c.) | c.987G>C |
| MANE Select transcript | [NM_018706](https://www.ncbi.nlm.nih.gov/nuccore/NM_018706) |
| dbSNP | [rs1363866819](https://www.ncbi.nlm.nih.gov/snp/rs1363866819/) |
| Variant type | single nucleotide variant |
| Location | chr10:12089255-12089255 (GRCh38) |
| ClinVar | [VCV1984701](https://www.ncbi.nlm.nih.gov/clinvar/variation/1984701/) |

**All HGVS expressions:** `NC_000010.10:g.12131254G>C`, `NC_000010.11:g.12089255G>C`, `NG_033248.1:g.25339G>C`, `NG_033248.2:g.25303G>C`, `NM_018706.7:c.987G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.801)
- REVEL 0.437 (indeterminate)
- SaProt LLR -10.281 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- SpliceAI predicts **donor loss** (Δ 0.96) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.387, GERP 0.918, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 36.0**. 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.*
- Regional missense constraint: **o/e 1.05** across the covering region of the MANE Select transcript (12,069,034–12,120,885), spanning 51,851 bp. Chi-square p 0.072. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.96**, acceptor gain **0.00**, donor gain **0.68**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.96**, acceptor gain **0.00**, donor gain **0.68**.
- Pangolin: Δ**0.82** (loss), gain 0.66 / loss 0.82. 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 **0.00134%** (afr) · FAF95 7.9e-05% · FAF99 5.4e-05% · 1/74,894 in the highest group · 5/1,611,722 alleles overall — very rare (popmax 0.00134%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00134% | 74,894 |
| European (non-Finnish) | 0.000339% | 294,626 |

*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 **329** lies in a β-strand.

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-09-23.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-09-23 |

## 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.

## 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 1984701). 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.*