# NM_000350.3(ABCA4):c.4223G>A (p.Trp1408Ter)

https://sugi.bio/variant/abca4-p-trp1408ter

## Summary

**ABCA4 p.Trp1408Ter (c.4223G>A)** is classified **Pathogenic** in ABCA4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-25). Absent from gnomAD v4.1; Associated with ABCA4-related disorder.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs61750134 · 2 submitters · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ABCA4 gene that is considered disease-causing, submitted by 2 submitters, and is linked to ABCA4-related disorder.

*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.*

**Support & next steps:** [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.Trp1408Ter |
| Coding change (HGVS c.) | c.4223G>A |
| MANE Select transcript | [NM_000350](https://www.ncbi.nlm.nih.gov/nuccore/NM_000350) |
| dbSNP | [rs61750134](https://www.ncbi.nlm.nih.gov/snp/rs61750134/) |
| Variant type | single nucleotide variant |
| Location | chr1:94031026-94031026 (GRCh38) |
| ClinVar | [VCV860842](https://www.ncbi.nlm.nih.gov/clinvar/variation/860842/) |

**All HGVS expressions:** `NC_000001.10:g.94496582C>T`, `NC_000001.11:g.94031026C>T`, `NG_009073.1:g.95124G>A`, `NG_009073.2:g.95122G>A`, `NM_000350.3:c.4223G>A`, `NM_001425324.1:c.4001G>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.27) — consistent with the pathogenic call
- Conservation: phyloP 7.68, GERP 2.66, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — 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.
- CADD: **PHRED 49.0**. 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 deltas (raw): acceptor loss **0.01**, donor loss **0.27**, acceptor gain **0.03**, donor gain **0.00**. Largest is donor loss, 30 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.03**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.40** (loss), gain 0.01 / loss 0.40. 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}

**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.

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 2025-01-25.

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

**Submission history:** 2 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-25 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-09-04 |

## Associated conditions {#conditions}

[ABCA4-related disorder](https://sugi.bio/atlas/disease/abca4-related-disorder/).

**Reported phenotype names (ClinVar):** ABCA4-related disorder, not provided, none provided, ABCA4-related condition, ABCA4-related disorders.

## Same-residue context {#hotspot}

Residue **1408** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [ABCA4 p.Trp1408fs](/variant/abca4-p-trp1408fs), [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.Trp1408Leu](/variant/abca4-p-trp1408leu), [ABCA4 c.1099+2T>G](/variant/abca4-c-1099-plus-2t-g), [ABCA4 c.160+5G>C](/variant/abca4-c-160-plus-5g-c), [ABCA4 c.1937+1G>C](/variant/abca4-c-1937-plus-1g-c), [ABCA4 c.1938-619A>G](/variant/abca4-c-1938-minus-619a-g), [ABCA4 c.2160+1G>C](/variant/abca4-c-2160-plus-1g-c), [ABCA4 c.2161-8G>A](/variant/abca4-c-2161-minus-8g-a), [ABCA4 c.2382+1G>A](/variant/abca4-c-2382-plus-1g-a).

### 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 860842). 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.*