# NM_000350.3(ABCA4):c.768G>A (p.Val256=)

https://sugi.bio/variant/abca4-p-val256

## Summary

**ABCA4 p.Val256= (c.768G>A)** is classified **Uncertain significance** in ABCA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-12). Absent from gnomAD v4.1; Associated with severe early-childhood-onset retinal dystrophy.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ABCA4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to severe early-childhood-onset 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy |
| Clinical trials | 14 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ABCA4 is a diagnostic-grade gene on 1 Genomics England panel |

**Commonly reported features of Severe early-childhood-onset retinal dystrophy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Visual impairment — Frequent (79-30%)
- Retinal degeneration — Frequent (79-30%)
- Nyctalopia — Frequent (79-30%)
- Undetectable electroretinogram — Frequent (79-30%)
- Nystagmus — Frequent (79-30%)
- Abnormal pupillary light reflex — Frequent (79-30%)
- Peripheral visual field loss — Frequent (79-30%)
- Optic disc pallor — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0021565/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.Val256= |
| Coding change (HGVS c.) | c.768G>A |
| MANE Select transcript | [NM_000350](https://www.ncbi.nlm.nih.gov/nuccore/NM_000350) |
| Variant type | single nucleotide variant |
| Location | chr1:94098794-94098794 (GRCh38) |
| ClinVar | [VCV4292814](https://www.ncbi.nlm.nih.gov/clinvar/variation/4292814/) |

**All HGVS expressions:** `NC_000001.10:g.94564350C>T`, `NC_000001.11:g.94098794C>T`, `NG_009073.1:g.27356G>A`, `NG_009073.2:g.27354G>A`, `NM_000350.3:c.768G>A`, `NM_001425324.1:c.768G>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 **donor loss** (Δ 0.54) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.654, GERP 1.9, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 21.5**. 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 **0.00**, donor loss **0.54**, acceptor gain **0.00**, donor gain **0.42**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.42**.
- Pangolin: Δ**0.54** (gain), gain 0.54 / loss 0.53. SpliceAI calls loss. 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 **256** 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).

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-02-12.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-12 |

## Associated conditions {#conditions}

[severe early-childhood-onset retinal dystrophy](https://sugi.bio/atlas/disease/severe-early-childhood-onset-retinal-dystrophy/).

**Reported phenotype names (ClinVar):** Severe early-childhood-onset retinal dystrophy, Stargardt macular dystrophy, Juvenile onset macular degeneration, Stargardt disease 1, MACULAR DYSTROPHY WITH FLECKS, TYPE 1, STGD.

## Similar variants {#similar}

Related ABCA4 variant pages (same residue, condition, or type): [ABCA4 p.Val256Leu](/variant/abca4-p-val256leu), [ABCA4 c.1937+1G>A](/variant/abca4-c-1937-plus-1g-a), [ABCA4 c.3523-1G>A](/variant/abca4-c-3523-minus-1g-a), [ABCA4 c.4253+43G>A](/variant/abca4-c-4253-plus-43g-a), [ABCA4 c.4254-1G>C](/variant/abca4-c-4254-minus-1g-c), [ABCA4 c.4352+1G>A](/variant/abca4-c-4352-plus-1g-a), [ABCA4 c.4773+3A>G](/variant/abca4-c-4773-plus-3a-g), [ABCA4 c.5018+2T>C](/variant/abca4-c-5018-plus-2t-c).

### 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 4292814). 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.*