# NM_001171.6(ABCC6):c.4252C>A (p.Arg1418=)

https://sugi.bio/variant/abcc6-p-arg1418

## Summary

**ABCC6 p.Arg1418= (c.4252C>A)** is classified **Uncertain significance** in ABCC6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-27). Absent from gnomAD v4.1; Associated with autosomal recessive inherited pseudoxanthoma elasticum.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs59588658 · 2 submitters · 3 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ABCC6 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, 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.Arg1418= |
| Coding change (HGVS c.) | c.4252C>A |
| MANE Select transcript | [NM_001171](https://www.ncbi.nlm.nih.gov/nuccore/NM_001171) |
| dbSNP | [rs59588658](https://www.ncbi.nlm.nih.gov/snp/rs59588658/) |
| Variant type | single nucleotide variant |
| Location | chr16:16150729-16150729 (GRCh38) |
| ClinVar | [VCV2099991](https://www.ncbi.nlm.nih.gov/clinvar/variation/2099991/) |

**All HGVS expressions:** `LRG_1115:g.77889C>A`, `LRG_1115t1:c.4252C>A`, `NC_000016.10:g.16150729G>T`, `NC_000016.9:g.16244586G>T`, `NG_007558.3:g.77889C>A`, `NM_001171.6:c.4252C>A`, `NM_001351800.1:c.3910C>A`, `NR_147784.1:n.3914C>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.77) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.493, GERP 0.692, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 22.7**. 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 deltas (raw): acceptor loss **0.10**, donor loss **0.00**, acceptor gain **0.77**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.10**, donor loss **0.00**, acceptor gain **0.77**, donor gain **0.00**.
- Pangolin: Δ**0.35** (gain), gain 0.35 / loss 0.17. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **1418** lies in the abc transporter 2 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.Arg1418= falls in the abc transporter 2 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-12-27.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-02-20 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-27 |

## Associated conditions {#conditions}

[autosomal recessive inherited pseudoxanthoma elasticum](https://sugi.bio/atlas/disease/autosomal-recessive-inherited-pseudoxanthoma-elasticum/), [pseudoxanthoma elasticum, forme fruste](https://sugi.bio/atlas/disease/pseudoxanthoma-elasticum-forme-fruste/), [arterial calcification, generalized, of infancy, 2](https://sugi.bio/atlas/disease/arterial-calcification-generalized-of-infancy-2/).

**Reported phenotype names (ClinVar):** Autosomal recessive inherited pseudoxanthoma elasticum, not provided, Arterial calcification, generalized, of infancy, 2, Pseudoxanthoma elasticum, forme fruste, none provided, Pseudoxanthoma Elasticum, Incomplete, PSEUDOXANTHOMA ELASTICUM, HETEROZYGOUS.

## Similar variants {#similar}

Related ABCC6 variant pages (same residue, condition, or type): [ABCC6 p.Arg1418Gln](/variant/abcc6-p-arg1418gln), [ABCC6 p.Arg1418Trp](/variant/abcc6-p-arg1418trp), [ABCC6 c.1868-5T>G](/variant/abcc6-c-1868-minus-5t-g), [ABCC6 c.2591-1G>T](/variant/abcc6-c-2591-minus-1g-t), [ABCC6 c.2787+1G>T](/variant/abcc6-c-2787-plus-1g-t), [ABCC6 c.3507-1G>A](/variant/abcc6-c-3507-minus-1g-a), [ABCC6 c.37-1G>A](/variant/abcc6-c-37-minus-1g-a), [ABCC6 c.3736-1G>A](/variant/abcc6-c-3736-minus-1g-a).

### 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 2099991). 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.*