# NM_173076.3(ABCA12):c.6858del (p.Phe2286fs)

https://sugi.bio/variant/abca12-p-phe2286fs

## Summary

**ABCA12 p.Phe2286fs (c.6858del)** is classified **Pathogenic** in ABCA12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-10). Ultra-rare (popmax 0.0112%, eas); Associated with autosomal recessive congenital ichthyosis 4A.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs751949857 · 2 submitters · 2 linked conditions · ultra-rare (popmax 0.0112%, eas)

## For patients & families {#patients}

This is a change in the ABCA12 gene that is considered disease-causing, submitted by 2 submitters, and is linked to autosomal recessive congenital ichthyosis 4A.

*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 dominant, Autosomal recessive |
| Age of onset (of this condition) | Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Diagnostic panels | ABCA12 is a diagnostic-grade gene on 4 Genomics England panels |

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

- Ectropion — Very frequent (99-80%)
- Dry skin — Very frequent (99-80%)
- Hyperkeratosis — Very frequent (99-80%)
- Pruritus — Very frequent (99-80%)
- Erythroderma — Very frequent (99-80%)
- Abnormality of the nail — Very frequent (99-80%)
- Ichthyosis — Very frequent (99-80%)
- Sparse hair — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009733/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ABCA12](https://sugi.bio/atlas/gene/ABCA12/) |
| Protein change (HGVS p.) | p.Phe2286fs |
| Coding change (HGVS c.) | c.6858del |
| MANE Select transcript | [NM_173076](https://www.ncbi.nlm.nih.gov/nuccore/NM_173076) |
| dbSNP | [rs751949857](https://www.ncbi.nlm.nih.gov/snp/rs751949857/) |
| Variant type | Deletion |
| Location | chr2:214949144-214949144 (GRCh38) |
| ClinVar | [VCV2734375](https://www.ncbi.nlm.nih.gov/clinvar/variation/2734375/) |

**All HGVS expressions:** `NC_000002.11:g.215813871del`, `NC_000002.12:g.214949147del`, `NG_007074.1:g.194284del`, `NG_007074.2:g.194482del`, `NM_015657.4:c.5904del`, `NM_173076.3:c.6858del`, `NR_103740.2:n.7356del`

## 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 7.689, GERP 2.39, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.582, pLI 4.8142e-17. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 46 of 53**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 34.0**. 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 **0.0112%** (eas) · FAF95 0.00435% · FAF99 0.00276% · 5/44,800 in the highest group · 5/1,612,464 alleles overall — ultra-rare (popmax 0.0112%, eas).

*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}

**ABCA12** population constraint: LOEUF 0.582, pLI 4.8142e-17, missense-Z 2.9254. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **2286** lies in the abc transporter 2 domain; a UniProt-annotated variant site (in arci4b); a UniProt-annotated variant site (in arci4b; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 68.32, 4% of residues very-high.

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

*Describes the biological roles of ABCA12 (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:** ABCA12's established molecular role includes signaling receptor binding. p.Phe2286fs falls in the abc transporter 2 domain. In Reactome, ABCA12 is annotated in disease pathway(s) including **Defective ABCA12 causes ARCI4B**.

**Disease mechanism (Reactome):** ABCA12 loss or alteration is curated in [Defective ABCA12 causes ARCI4B](https://reactome.org/content/detail/R-HSA-5682294).

### Pathways affected {#pathways}

ABCA12 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ABCA12 causes ARCI4B](https://reactome.org/content/detail/R-HSA-5682294) | curated |
| [ABC transporters in lipid homeostasis](https://reactome.org/content/detail/R-HSA-1369062) | curated |

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

**Molecular function:** signaling receptor binding, lipid carrier activity, apolipoprotein A-I receptor binding.

**Biological process:** corneocyte desquamation, ceramide metabolic process, lipid transport, intracellular protein transport, positive regulation of cholesterol efflux, secretion by cell.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-10.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-10 |

## Associated conditions {#conditions}

[autosomal recessive congenital ichthyosis 4A](https://sugi.bio/atlas/disease/autosomal-recessive-congenital-ichthyosis-4a/), [autosomal recessive congenital ichthyosis 4B](https://sugi.bio/atlas/disease/autosomal-recessive-congenital-ichthyosis-4b/).

**Reported phenotype names (ClinVar):** Autosomal recessive congenital ichthyosis 4A, not provided, Autosomal recessive congenital ichthyosis 4B, none provided, ICHTHYOSIS CONGENITA IIB, HARLEQUIN ICHTHYOSIS, ICHTHYOSIS CONGENITA, HARLEQUIN FETUS TYPE, Ichthyosis, congenital, autosomal recessive 4B (harlequin), Harlequin Fetus.

## Similar variants {#similar}

Related ABCA12 variant pages (same residue, condition, or type): [ABCA12 p.Asn528fs](/variant/abca12-p-asn528fs), [ABCA12 p.Val2442fs](/variant/abca12-p-val2442fs), [ABCA12 c.5469_5472del](/variant/abca12-c-5469-5472del), [ABCA12 p.Arg1461fs](/variant/abca12-p-arg1461fs), [ABCA12 p.Arg248fs](/variant/abca12-p-arg248fs), [ABCA12 p.Glu1932fs](/variant/abca12-p-glu1932fs), [ABCA12 p.Glu886fs](/variant/abca12-p-glu886fs), [ABCA12 p.Leu217_Leu218insTer](/variant/abca12-p-leu217-leu218inster).

### 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 2734375). 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.*