# NM_000350.3(ABCA4):c.6445C>T (p.Arg2149Ter)

https://sugi.bio/variant/abca4-p-arg2149ter

## Summary

**ABCA4 p.Arg2149Ter (c.6445C>T)** is classified **Pathogenic** in ABCA4 (ClinVar, Expert panel, 14 submitters; last evaluated 2025-12-05). Very rare (popmax 0.00891%, eas); Associated with ABCA4-related retinopathy.

**At a glance:** Pathogenic · review: Expert panel · rsID rs61750654 · 14 submitters · 6 linked conditions · very rare (popmax 0.00891%, eas)

## For patients & families {#patients}

This is a change in the ABCA4 gene that is considered disease-causing, submitted by 14 submitters, and is linked to ABCA4-related retinopathy.

*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 | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026556/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.Arg2149Ter |
| Coding change (HGVS c.) | c.6445C>T |
| MANE Select transcript | [NM_000350](https://www.ncbi.nlm.nih.gov/nuccore/NM_000350) |
| dbSNP | [rs61750654](https://www.ncbi.nlm.nih.gov/snp/rs61750654/) |
| Variant type | single nucleotide variant |
| Location | chr1:94000870-94000870 (GRCh38) |
| ClinVar | [VCV99460](https://www.ncbi.nlm.nih.gov/clinvar/variation/99460/) |

**All HGVS expressions:** `NC_000001.10:g.94466426G>A`, `NC_000001.11:g.94000870G>A`, `NG_009073.1:g.125280C>T`, `NG_009073.2:g.125278C>T`, `NM_000350.3:c.6445C>T`, `NM_001425324.1:c.6223C>T`

## 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 8.475, GERP -0.445, 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 47 of 50**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 54.0**. 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** — 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.
- Pangolin: Δ**0.29** (loss), gain 0.04 / loss 0.29. Not in the SpliceAI release. 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 (gnomAD v4.1): grpmax **0.00891%** (eas) · FAF95 0.00298% · FAF99 0.0018% · 4/44,890 in the highest group · 10/1,614,050 alleles overall — very rare (popmax 0.00891%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00891% | 11,223 |
| African / African-American | 0.00133% | 74,918 |
| South Asian | 0.0011% | 91,084 |
| European (non-Finnish) | 0.000339% | 295,010 |

*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 **2149** 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 abc transporter 2 domain; 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); a UniProt-annotated variant site (in stgd1); a β-strand.

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.Arg2149Ter falls in the abc transporter 2 domain. 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 Expert panel *(reviewed by expert panel)*, last evaluated 2025-12-05.

**Submitter consensus:** conflicting (11 Pathogenic, 2 Likely pathogenic, 1 not provided).

**Submission history:** 14 submissions (2014–2025); classifications have differed over time.

**ClinGen expert panel:** Pathogenic — ABCA4 VCEP (ABCA4-related retinopathy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PVS1`, `PM3_Supporting`, `PM2_Supporting`, `PS4`.
*Considered but not met:* `BS1`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000350.3:c.6445C>T (p.Arg2149Ter) variant in ABCA4 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 47 out of 50 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The total minor allele frequency in gnomAD v4.1.0 is 0.000006196 (10/1614050 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls with and OR of 86.3 and the CI is 30.40-338.60, which is above the ABCA4 VCEP threshold of >5, where the CI does not contain 1 (PS4; PMID: 35120629). This variant has been detected in at least 1 individual who was homozygous for the variant (PMID: 36284460; PM3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for ABCA4-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP: PVS1, PS4, PM3_Supporting, PM2_Supporting.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50140 · approved 2025-12-05 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/2a28d610-baee-43f6-9eef-6d2f37a33593).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Pathogenic | criteria provided, single submitter | clinical testing | 2021-01-01 |
| Eurofins Ntd Llc (ga) | Pathogenic | criteria provided, single submitter | clinical testing | 2017-09-28 |
| Retina International | not provided | no classification provided | not provided |  |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Pathogenic | criteria provided, single submitter | clinical testing | 2014-11-17 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2022-01-20 |
| Dept Of Ophthalmology, Nagoya University | Pathogenic | criteria provided, single submitter | research | 2023-10-01 |
| Neuberg Centre For Genomic Medicine, NCGM | Pathogenic | criteria provided, single submitter | clinical testing | 2023-05-20 |
| PreventionGenetics, part of Exact Sciences | Pathogenic | no assertion criteria provided | clinical testing | 2024-06-11 |
| NIHR Bioresource Rare Diseases, University of Cambridge | Likely pathogenic | no assertion criteria provided | research | 2015-01-01 |
| Department of Ophthalmology and Visual Sciences Kyoto University | Pathogenic | no assertion criteria provided | not provided |  |
| ClinGen ABCA4 Variant Curation Expert Panel, Clingen | Pathogenic | reviewed by expert panel | curation | 2025-12-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-12 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-22 |
| SingHealth Duke-NUS Institute of Precision Medicine | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-02-05 |

## Associated conditions {#conditions}

[ABCA4-related retinopathy](https://sugi.bio/atlas/disease/abca4-related-retinopathy/), [blindness (disorder)](https://sugi.bio/atlas/disease/blindness-disorder/), [macular degeneration](https://sugi.bio/atlas/disease/macular-degeneration/), [severe early-childhood-onset retinal dystrophy](https://sugi.bio/atlas/disease/severe-early-childhood-onset-retinal-dystrophy/), [retinitis pigmentosa 19](https://sugi.bio/atlas/disease/retinitis-pigmentosa-19/), [inherited retinal dystrophy](https://sugi.bio/atlas/disease/inherited-retinal-dystrophy/).

**Reported phenotype names (ClinVar):** ABCA4-related retinopathy, not provided, Severe early-childhood-onset retinal dystrophy, Retinal dystrophy, Blindness, Macular degeneration, Visual loss, Retinitis pigmentosa 19, ABCA4-related disorder, ABCA4-related retinoapthy.

## Same-residue context {#hotspot}

Residue **2149** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ABCA4 p.Arg2149Leu](/variant/abca4-p-arg2149leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ABCA4 variant pages (same residue, condition, or type): [ABCA4 p.Arg2149Gln](/variant/abca4-p-arg2149gln), [ABCA4 p.Arg2149Leu](/variant/abca4-p-arg2149leu), [ABCA4 p.Arg2149Pro](/variant/abca4-p-arg2149pro), [ABCA4 c.1937+1G>A](/variant/abca4-c-1937-plus-1g-a), [ABCA4 c.3328+2T>A](/variant/abca4-c-3328-plus-2t-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).

### 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 99460). 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.*