# NM_000350.3(ABCA4):c.6415C>T (p.Arg2139Trp)

https://sugi.bio/variant/abca4-p-arg2139trp

## Summary

**ABCA4 p.Arg2139Trp (c.6415C>T)** is classified **Pathogenic** in ABCA4 (ClinVar, Expert panel, 7 submitters; last evaluated 2025-12-05). AlphaMissense: likely pathogenic (0.8278); Very rare (popmax 0.0022%, sas); Associated with ABCA4-related retinopathy.

**At a glance:** Pathogenic · review: Expert panel · rsID rs61750653 · 7 submitters · 4 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.0022%, sas)

## For patients & families {#patients}

This is a change in the ABCA4 gene that is considered disease-causing, submitted by 7 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.Arg2139Trp |
| Coding change (HGVS c.) | c.6415C>T |
| MANE Select transcript | [NM_000350](https://www.ncbi.nlm.nih.gov/nuccore/NM_000350) |
| dbSNP | [rs61750653](https://www.ncbi.nlm.nih.gov/snp/rs61750653/) |
| Variant type | single nucleotide variant |
| Location | chr1:94000900-94000900 (GRCh38) |
| ClinVar | [VCV99458](https://www.ncbi.nlm.nih.gov/clinvar/variation/99458/) |

**All HGVS expressions:** `NC_000001.10:g.94466456G>A`, `NC_000001.11:g.94000900G>A`, `NG_009073.1:g.125250C>T`, `NG_009073.2:g.125248C>T`, `NM_000350.3:c.6415C>T`, `NM_001425324.1:c.6193C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.8278) — concordant with the pathogenic call
- REVEL 0.975 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.128 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 4.376, GERP -0.445, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 30.0**. 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.*
- Regional missense constraint: **o/e 0.98** across the covering region of the MANE Select transcript (93,993,240–94,121,045), spanning 127,805 bp. Chi-square p 0.24. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for ABCA4 (2,774 scored positions, the nearest 13 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.0022%** (sas) · FAF95 0.000615% · FAF99 0.000474% · 2/91,090 in the highest group · 18/1,614,184 alleles overall — very rare (popmax 0.0022%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,255 |
| South Asian (grpmax) | 0.0022% | 45,545 |
| African / African-American | 0.00133% | 75,042 |
| European (non-Finnish) | 0.0011% | 90,771 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **2139** 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.Arg2139Trp 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 (4 Pathogenic, 2 Likely pathogenic, 1 not provided).

**Submission history:** 7 submissions (2016–2025); 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):** `PP3_Moderate`, `PM2_Supporting`, `PS4`, `PM3_Strong`.
*Considered but not met:* `PP4`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000350.3(ABCA4):c.6415C>T variant in ABCA4 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 2139 (p.Arg2139Trp). The total minor allele frequency in gnomAD v4.1.0 is 0.00001115 (18/1614184 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001). The computational predictor REVEL gives a score of 0.975 which is above the threshold of >0.772, evidence that predicts a damaging effect on ABCA4 function (PP3_Moderate). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls with an OR of 35.7 and the CI is 2.87-1852.51, 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 3 individuals with ABCA4-related retinopathy who were all compound heterozygous for the variant and a pathogenic variant (c.5018+2T>C, c.2345G>A; p.Trp782Ter), c.3994C>T; p.Gln1332Ter) with 1 of those was confirmed in trans by family testing (PM3_Strong; PMIDs: 37498587, 38602673). 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 (Specification Version 1.0): PS4, PM3_Strong, PM2_Supporting, PP3_Moderate.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50140 · approved 2025-12-05 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/0da4793f-a666-4f88-acd4-147615b10c1d).*
*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 |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | no assertion criteria provided | clinical testing | 2024-06-06 |
| ClinGen ABCA4 Variant Curation Expert Panel, Clingen | Pathogenic | reviewed by expert panel | curation | 2025-12-05 |
| Retina International | not provided | no classification provided | not provided |  |
| Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Likely pathogenic | criteria provided, single submitter | clinical testing | 2016-01-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-13 |
| Juno Genomics, Hangzhou Juno Genomics, Inc | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-23 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** ABCA4-related retinopathy, not provided, Retinal dystrophy, Severe early-childhood-onset retinal dystrophy, ABCA4-related disorder, Retinitis pigmentosa, ABCA4 retinoapthy, ABCA4-related retinoapthy, Inherited retinal dystrophy, ABCA4-related disorders.

## Same-residue context {#hotspot}

Residue **2139** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [ABCA4 p.Arg2139Gln](/variant/abca4-p-arg2139gln), [ABCA4 p.Arg2139Pro](/variant/abca4-p-arg2139pro). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ABCA4 variant pages (same residue, condition, or type): [ABCA4 p.Arg2139Gln](/variant/abca4-p-arg2139gln), [ABCA4 p.Arg2139Pro](/variant/abca4-p-arg2139pro), [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), [ABCA4 c.4352+1G>A](/variant/abca4-c-4352-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 99458). 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.*