# NM_000350.3(ABCA4):c.6732G>A (p.Val2244=)

https://sugi.bio/variant/abca4-p-val2244

## Summary

**ABCA4 p.Val2244= (c.6732G>A)** is classified **Benign/Likely benign** in ABCA4 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-06-26). Common (popmax 8.56%, afr) — too common for a highly-penetrant pathogenic allele; Associated with inherited retinal dystrophy.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs77293072 · 10 submitters · 1 linked condition · common (popmax 8.56%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the ABCA4 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 10 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.Val2244= |
| Coding change (HGVS c.) | c.6732G>A |
| MANE Select transcript | [NM_000350](https://www.ncbi.nlm.nih.gov/nuccore/NM_000350) |
| dbSNP | [rs77293072](https://www.ncbi.nlm.nih.gov/snp/rs77293072/) |
| Variant type | single nucleotide variant |
| Location | chr1:93996193-93996193 (GRCh38) |
| ClinVar | [VCV99492](https://www.ncbi.nlm.nih.gov/clinvar/variation/99492/) |

**All HGVS expressions:** `NC_000001.10:g.94461749C>T`, `NC_000001.11:g.93996193C>T`, `NG_009073.1:g.129957G>A`, `NG_009073.2:g.129955G>A`, `NM_000350.3:c.6732G>A`, `NM_001425324.1:c.6510G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 8.56%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 -2.669, GERP -3.68 — fast-evolving / accelerated position
- CADD: **PHRED 0.122**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.56%** (afr) · FAF95 8.38% · FAF99 8.31% · 6,400/74,810 in the highest group · 7,388/1,611,904 alleles overall — common (popmax 8.56%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 8.56% | 12 |
| Admixed American | 0.626% | 160 |
| Remaining individuals (not grpmax-eligible) | 0.57% | 175 |
| Middle Eastern | 0.496% | 202 |
| European (non-Finnish) | 0.0178% | 5,612 |
| South Asian | 0.0176% | 5,691 |

*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 **2244** 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); the 'essential for atp binding and atpase activity' region; a UniProt-annotated variant site (in stgd1 and cord3; uncertain significance); a UniProt-annotated variant site (sequence variant); a UniProt-annotated variant site (in stgd1 and ffm; uncertain significance); a UniProt-annotated variant site (in stgd1; uncertain significance; also found in a patient with chorioretinal atrophy; uncertain significance); 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. p.Val2244= falls in the essential for atp binding and atpase activity region. 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-26.

**Submitter consensus:** conflicting (6 Benign, 3 Likely benign, 1 not provided).

**Submission history:** 10 submissions (2011–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2011-07-18 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2022-10-21 |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2015-06-11 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2026-06-26 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-25 |
| Retina International | not provided | no classification provided | not provided |  |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Likely benign | criteria provided, single submitter | clinical testing | 2023-01-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-02 |

## Associated conditions {#conditions}

[inherited retinal dystrophy](https://sugi.bio/atlas/disease/inherited-retinal-dystrophy/).

**Reported phenotype names (ClinVar):** Retinal dystrophy, not provided, not specified, ABCA4-related disorder, AllHighlyPenetrant, Inherited retinal dystrophy, none provided, ABCA4-related disorders, ABCA4-related condition.

## Same-residue context {#hotspot}

Residue **2244** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ABCA4 p.Val2244Glu](/variant/abca4-p-val2244glu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ABCA4 variant pages (same residue, condition, or type): [ABCA4 p.Val2244Glu](/variant/abca4-p-val2244glu), [ABCA4 c.1937+1G>A](/variant/abca4-c-1937-plus-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>A](/variant/abca4-c-5018-plus-2t-a), [ABCA4 c.5018+2T>C](/variant/abca4-c-5018-plus-2t-c).

### 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 99492). 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.*