# NM_001082971.2(DDC):c.1233del (p.Arg412fs)

https://sugi.bio/variant/ddc-p-arg412fs

## Summary

**DDC p.Arg412fs (c.1233del)** is classified **Pathogenic** in DDC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-04). Very rare (popmax 0.000254%, nfe); Associated with aromatic L-amino acid decarboxylase deficiency.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1344017069 · 1 submitter · 1 linked condition · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the DDC gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, 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/) |
| Protein change (HGVS p.) | p.Arg412fs |
| Coding change (HGVS c.) | c.1233del |
| MANE Select transcript | [NM_001082971](https://www.ncbi.nlm.nih.gov/nuccore/NM_001082971) |
| dbSNP | [rs1344017069](https://www.ncbi.nlm.nih.gov/snp/rs1344017069/) |
| Variant type | Deletion |
| Location | chr7:50467223-50467223 (GRCh38) |
| ClinVar | [VCV1374428](https://www.ncbi.nlm.nih.gov/clinvar/variation/1374428/) |

**All HGVS expressions:** `NC_000007.13:g.50534923del`, `NC_000007.14:g.50467225del`, `NG_008742.1:g.103234del`, `NM_000790.4:c.1233del`, `NM_001082971.2:c.1233del`, `NM_001242886.2:c.1119del`, `NM_001242887.2:c.1089del`, `NM_001242888.2:c.999del`, `NM_001242889.2:c.954del`

## 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 5.69, GERP 2.29, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.922, pLI 7.7907e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 13 of 15**, 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 (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,179,630 in the highest group · 4/1,613,664 alleles overall — very rare (popmax 0.000254%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,486 |
| European (non-Finnish) (grpmax) | 0.000254% | 393,210 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

Residue **412** lies in a β-strand.

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** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-04.

**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 | 2025-05-04 |

## 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, AADC DEFICIENCY, DDC DEFICIENCY, DOPA DECARBOXYLASE DEFICIENCY, Aromatic L-Amino Acid Decarboxylase Deficiency, Aromatic amino acid decarboxylase deficiency.

## Same-residue context {#hotspot}

Residue **412** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DDC p.Arg412Trp](/variant/ddc-p-arg412trp). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DDC variant pages (same residue, condition, or type): [DDC p.Arg412Trp](/variant/ddc-p-arg412trp), [DDC p.Arg412Gln](/variant/ddc-p-arg412gln), [DDC c.316del](/variant/ddc-c-316del), [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.Met362_Trp363insTer](/variant/ddc-p-met362-trp363inster), [DDC p.Met362fs](/variant/ddc-p-met362fs).

### 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 1374428). 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.*