# NM_000350.3(ABCA4):c.4222del (p.Trp1408fs)

https://sugi.bio/variant/abca4-p-trp1408fs

## Summary

**ABCA4 p.Trp1408fs (c.4222del)** is classified **Pathogenic** in ABCA4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-01-01). Very rare (popmax 0.0011%, sas); Associated with inherited retinal dystrophy.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1571264574 · 3 submitters · 3 linked conditions · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the ABCA4 gene that is considered disease-causing, submitted by 3 submitters, and is linked to inherited retinal dystrophy.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 40 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018916/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ABCA4](https://sugi.bio/atlas/gene/ABCA4/) |
| Protein change (HGVS p.) | p.Trp1408fs |
| Coding change (HGVS c.) | c.4222del |
| MANE Select transcript | [NM_000350](https://www.ncbi.nlm.nih.gov/nuccore/NM_000350) |
| dbSNP | [rs1571264574](https://www.ncbi.nlm.nih.gov/snp/rs1571264574/) |
| Variant type | Deletion |
| Location | chr1:94031027-94031027 (GRCh38) |
| ClinVar | [VCV636147](https://www.ncbi.nlm.nih.gov/clinvar/variation/636147/) |

**All HGVS expressions:** `NC_000001.10:g.94496583del`, `NC_000001.11:g.94031027del`, `NG_009073.1:g.95123del`, `NG_009073.2:g.95121del`, `NM_000350.3:c.4222del`, `NM_001425324.1:c.4000delT`

## 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 7.68, GERP 2.66, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.786, pLI 3.4822e-43. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 28 of 50**, 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 **0.0011%** (sas) · 1/91,056 in the highest group · 1/1,461,804 alleles overall — very rare (popmax 0.0011%, sas).

*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}

**ABCA4** population constraint: LOEUF 0.786, pLI 3.4822e-43, missense-Z 1.3815. *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):

- **ABCA4-related retinopathy** — Definitive (AR)
- **age related macular degeneration 2** — Disputed (AD)

## Protein context {#protein}

Residue **1408** lies in a UniProt-annotated variant site (in cord3; uncertain significance); a UniProt-annotated variant site (in stgd1; uncertain significance); a UniProt-annotated variant site (found in a patient with chorioretinal atrophy; uncertain significance); a UniProt-annotated variant site (found in a patient with macular dystrophy; uncertain significance); a UniProt-annotated variant site (in stgd1; likely pathogenic; does not affect secondary structure; decreased all-trans-retinal binding); a UniProt-annotated variant site (in stgd1; likely pathogenic; reduced retinal-stimulated atp hydrolysis); an α-helix; a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 75.96, 10% of residues very-high.

**8 experimental structure(s)** (PDB): [7E7I](https://www.rcsb.org/structure/7E7I), [7E7O](https://www.rcsb.org/structure/7E7O), [7E7Q](https://www.rcsb.org/structure/7E7Q), [7LKP](https://www.rcsb.org/structure/7LKP), [7LKZ](https://www.rcsb.org/structure/7LKZ), [7M1P](https://www.rcsb.org/structure/7M1P).

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

*Describes the biological roles of ABCA4 (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:** ABCA4's established molecular role includes 11-cis retinal binding. In Reactome, ABCA4 is annotated in disease pathway(s) including **Defective visual phototransduction due to ABCA4 loss of function**.

**Disease mechanism (Reactome):** ABCA4 loss or alteration is curated in [Defective visual phototransduction due to ABCA4 loss of function](https://reactome.org/content/detail/R-HSA-9918454).

### Pathways affected {#pathways}

ABCA4 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective visual phototransduction due to ABCA4 loss of function](https://reactome.org/content/detail/R-HSA-9918454) | curated |
| [ABC-family protein mediated transport](https://reactome.org/content/detail/R-HSA-382556) | curated |
| [The canonical retinoid cycle in rods (twilight vision)](https://reactome.org/content/detail/R-HSA-2453902) | electronic |

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

**Molecular function:** 11-cis retinal binding, all-trans retinal binding, ATP hydrolysis activity, phosphatidylethanolamine flippase activity, flippase activity.

**Biological process:** retinal metabolic process, phospholipid translocation.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-01-01.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Likely pathogenic).

**Submission history:** 3 submissions (2016–2021); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Likely pathogenic | no assertion criteria provided | research | 2018-04-01 |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Pathogenic | criteria provided, single submitter | clinical testing | 2016-01-01 |
| Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Pathogenic | criteria provided, single submitter | clinical testing | 2021-01-01 |

## Associated conditions {#conditions}

[inherited retinal dystrophy](https://sugi.bio/atlas/disease/inherited-retinal-dystrophy/), [age related macular degeneration 2](https://sugi.bio/atlas/disease/age-related-macular-degeneration-2/), [Stargardt disease](https://sugi.bio/atlas/disease/stargardt-disease/).

**Reported phenotype names (ClinVar):** Retinal dystrophy, Stargardt disease, Age related macular degeneration 2, Stargardt's disease, Fundus flavimaculatus, Inherited retinal dystrophy, MACULOPATHY, AGE-RELATED, MACULAR DEGENERATION, SENILE, MACULOPATHY, AGE-RELATED, 2.

## Same-residue context {#hotspot}

Residue **1408** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [ABCA4 p.Trp1408Ter](/variant/abca4-p-trp1408ter), [ABCA4 p.Trp1408Leu](/variant/abca4-p-trp1408leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ABCA4 variant pages (same residue, condition, or type): [ABCA4 p.Asp279fs](/variant/abca4-p-asp279fs), [ABCA4 p.Gly1972_Val1973insTer](/variant/abca4-p-gly1972-val1973inster), [ABCA4 p.Leu296fs](/variant/abca4-p-leu296fs), [ABCA4 p.Lys1033fs](/variant/abca4-p-lys1033fs), [ABCA4 p.Ser1642fs](/variant/abca4-p-ser1642fs), [ABCA4 c.6729+5_6729+19del](/variant/abca4-c-6729-plus-5-6729-plus-19del), [ABCA4 p.Asp342fs](/variant/abca4-p-asp342fs), [ABCA4 p.Gln1513fs](/variant/abca4-p-gln1513fs).

### 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 636147). 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.*