# NM_000790.4(DDC):c.316del

https://sugi.bio/variant/ddc-c-316del

## Summary

**DDC c.316del** is classified **Pathogenic/Likely pathogenic** in DDC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-18). Very rare (popmax 0.000593%, nfe); Associated with aromatic L-amino acid decarboxylase deficiency.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1364054304 · 2 submitters · 1 linked condition · very rare (popmax 0.000593%, nfe)

## For patients & families {#patients}

This is a change in the DDC gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to aromatic L-amino acid decarboxylase deficiency.

*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) | Infancy, Neonatal |
| Clinical trials | 9 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DDC is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of Aromatic L-amino acid decarboxylase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Global developmental delay — Very frequent (99-80%)
- Decreased CSF homovanillic acid concentration — Very frequent (99-80%)
- Decreased CSF 5-hydroxyindolacetic acid concentration — Very frequent (99-80%)
- Atypical behavior — Frequent (79-30%)
- Irritability — Frequent (79-30%)
- Hyperhidrosis — Frequent (79-30%)
- Intellectual disability — Frequent (79-30%)
- Seizure — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000770/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DDC](https://sugi.bio/atlas/gene/DDC/) |
| Coding change (HGVS c.) | c.316del |
| MANE Select transcript | [NM_001082971](https://www.ncbi.nlm.nih.gov/nuccore/NM_001082971) (variant reported on NM_000790) |
| dbSNP | [rs1364054304](https://www.ncbi.nlm.nih.gov/snp/rs1364054304/) |
| Variant type | Deletion |
| Location | chr7:50537979-50537979 (GRCh38) |
| ClinVar | [VCV1399541](https://www.ncbi.nlm.nih.gov/clinvar/variation/1399541/) |

**All HGVS expressions:** `NC_000007.13:g.50605678del`, `NC_000007.14:g.50537980del`, `NG_008742.1:g.32478del`, `NG_008742.2:g.32426del`, `NM_000790.4:c.316del`, `NM_001242888.2:c.201+5906del`

## 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 6.369, GERP 1.43, phastCons 1 — highly conserved position (PP3-type support)
- 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 **0.000593%** (nfe) · FAF95 0.000247% · FAF99 0.000159% · 7/1,180,038 in the highest group · 7/1,614,016 alleles overall — very rare (popmax 0.000593%, nfe).

*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}

**DDC** population constraint: LOEUF 0.922, pLI 7.7907e-10, missense-Z 1.0856. *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):

- **aromatic L-amino acid decarboxylase deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 96.88, 96% of residues very-high.

**8 experimental structure(s)** (PDB): [3RBF](https://www.rcsb.org/structure/3RBF), [3RBL](https://www.rcsb.org/structure/3RBL), [3RCH](https://www.rcsb.org/structure/3RCH), [8OR9](https://www.rcsb.org/structure/8OR9), [8ORA](https://www.rcsb.org/structure/8ORA), [9GNS](https://www.rcsb.org/structure/9GNS) — incl. mutant structure 9HRH.

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

*Describes the biological roles of DDC (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:** DDC's established molecular role includes aromatic-L-amino-acid decarboxylase activity.


### Pathways affected {#pathways}

DDC participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Catecholamine biosynthesis](https://reactome.org/content/detail/R-HSA-209905) | other |
| [Serotonin and melatonin biosynthesis](https://reactome.org/content/detail/R-HSA-209931) | other |

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

**Molecular function:** aromatic-L-amino-acid decarboxylase activity, enzyme binding, 5-hydroxy-L-tryptophan decarboxylase activity, L-dopa decarboxylase activity.

**Biological process:** dopamine biosynthetic process.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-18.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-03-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-18 |

## Associated conditions {#conditions}

[aromatic L-amino acid decarboxylase deficiency](https://sugi.bio/atlas/disease/aromatic-l-amino-acid-decarboxylase-deficiency/).

**Reported phenotype names (ClinVar):** Deficiency of aromatic-L-amino-acid decarboxylase, Aromatic L-Amino Acid Decarboxylase Deficiency, Aromatic amino acid decarboxylase deficiency, AADC DEFICIENCY, DDC DEFICIENCY, DOPA DECARBOXYLASE DEFICIENCY.

## Similar variants {#similar}

Related DDC variant pages (same residue, condition, or type): [DDC p.Pro352fs](/variant/ddc-p-pro352fs), [DDC p.Pro43fs](/variant/ddc-p-pro43fs), [DDC c.435+8518_435+8519del](/variant/ddc-c-435-plus-8518-435-plus-8519del), [DDC p.Arg412fs](/variant/ddc-p-arg412fs), [DDC p.Met362_Trp363insTer](/variant/ddc-p-met362-trp363inster), [DDC p.Met362fs](/variant/ddc-p-met362fs), [DDC p.Met89fs](/variant/ddc-p-met89fs), [DDC p.Pro81fs](/variant/ddc-p-pro81fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 1399541). 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.*