# NM_001171.6(ABCC6):c.2350del (p.Asp784fs)

https://sugi.bio/variant/abcc6-p-asp784fs

## Summary

**ABCC6 p.Asp784fs (c.2350del)** is classified **Likely pathogenic** in ABCC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-19). Associated with autosomal recessive inherited pseudoxanthoma elasticum.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the ABCC6 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to autosomal recessive inherited pseudoxanthoma elasticum.

*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) | All ages |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 28 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ABCC6 is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Pseudoxanthoma elasticum** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Thickened nuchal skin fold — Very frequent (99-80%)
- Retinopathy — Very frequent (99-80%)
- Retinal hemorrhage — Very frequent (99-80%)
- Abnormality of the skin — Very frequent (99-80%)
- Angioid streaks of the fundus — Very frequent (99-80%)
- Excessive wrinkled skin — Very frequent (99-80%)
- Abnormal cardiovascular system morphology — Very frequent (99-80%)
- Arterial stenosis — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024699/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ABCC6](https://sugi.bio/atlas/gene/ABCC6/) |
| Protein change (HGVS p.) | p.Asp784fs |
| Coding change (HGVS c.) | c.2350del |
| MANE Select transcript | [NM_001171](https://www.ncbi.nlm.nih.gov/nuccore/NM_001171) |
| Variant type | Deletion |
| Location | chr16:16178863-16178863 (GRCh38) |
| ClinVar | [VCV3393229](https://www.ncbi.nlm.nih.gov/clinvar/variation/3393229/) |

**All HGVS expressions:** `LRG_1115:g.49755del`, `LRG_1115t1:c.2350del`, `NC_000016.10:g.16178864del`, `NC_000016.9:g.16272721del`, `NG_007558.3:g.49755del`, `NM_001171.6:c.2350del`, `NM_001351800.1:c.2008del`, `NR_147784.1:n.2387del`

## 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 7.891, GERP 1.84, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.917, pLI 1.2351e-33. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 18 of 31**, 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.

*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}

**ABCC6** population constraint: LOEUF 0.917, pLI 1.2351e-33, missense-Z 1.031. *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):

- **inherited pseudoxanthoma elasticum** — Definitive (SD)

## Protein context {#protein}

Residue **784** lies in the abc transporter 1 domain.

AlphaFold model confidence (whole protein): pLDDT 81.32, 29% of residues very-high.

**4 experimental structure(s)** (PDB): [6BZR](https://www.rcsb.org/structure/6BZR), [6BZS](https://www.rcsb.org/structure/6BZS), [6NLO](https://www.rcsb.org/structure/6NLO), [6P7F](https://www.rcsb.org/structure/6P7F) — incl. mutant structure 6P7F.

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

*Describes the biological roles of ABCC6 (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:** ABCC6's established molecular role includes ATP binding. p.Asp784fs falls in the abc transporter 1 domain. In Reactome, ABCC6 is annotated in disease pathway(s) including **Defective ABCC6 causes PXE**.

**Disease mechanism (Reactome):** ABCC6 loss or alteration is curated in [Defective ABCC6 causes PXE](https://reactome.org/content/detail/R-HSA-5690338).

### Pathways affected {#pathways}

ABCC6 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ABCC6 causes PXE](https://reactome.org/content/detail/R-HSA-5690338) | curated |
| [ABC-family protein mediated transport](https://reactome.org/content/detail/R-HSA-382556) | curated |

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

**Molecular function:** ATP binding, ABC-type glutathione S-conjugate transporter activity, ATPase-coupled transmembrane transporter activity.

**Biological process:** gene expression, ATP transport, ATP metabolic process, phosphate ion homeostasis, calcium ion homeostasis, leukotriene transport.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-19.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-12-19 |

## Associated conditions {#conditions}

[autosomal recessive inherited pseudoxanthoma elasticum](https://sugi.bio/atlas/disease/autosomal-recessive-inherited-pseudoxanthoma-elasticum/).

**Reported phenotype names (ClinVar):** Autosomal recessive inherited pseudoxanthoma elasticum.

## Similar variants {#similar}

Related ABCC6 variant pages (same residue, condition, or type): [ABCC6 c.2248-2_2248-1del](/variant/abcc6-c-2248-minus-2-2248-minus-1del), [ABCC6 c.3506+2_3506+5del](/variant/abcc6-c-3506-plus-2-3506-plus-5del), [ABCC6 c.998+2_998+3del](/variant/abcc6-c-998-plus-2-998-plus-3del), [ABCC6 p.Ala667fs](/variant/abcc6-p-ala667fs), [ABCC6 p.Arg473fs](/variant/abcc6-p-arg473fs), [ABCC6 p.Asp1368fs](/variant/abcc6-p-asp1368fs), [ABCC6 p.Glu559fs](/variant/abcc6-p-glu559fs), [ABCC6 p.Leu775fs](/variant/abcc6-p-leu775fs).

### 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 3393229). 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.*