ABCA4 p.Arg653Cys
c.1957C>T · rs61749420 · VCV99108
ClinGen expert panel — ABCA4 VCEP
Pathogenic for ABCA4-related retinopathy. Applied ACMG criteria (verbatim):
PP3_Moderate PM2_Supporting PS3_Supporting PS4 PM3
Curation rationale (ClinGen, verbatim)
The NM_000350.3:c.1957C>T variant in ABCA4 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 653 (p.Arg653Cys). The total minor allele frequency in gnomAD v4.1.0 is 0.00002666 (43/1612644 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001). The computational predictor REVEL gives a score of 0.852 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. The OR is 139.4 and the CI is 43.93-707.41, 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 4 individuals with ABCA4-related retinopathy. Of those individuals, 2 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant unconfirmed in trans (c.3386G>T; p.(Arg1129Leu)( PM3; PMID:35119454). ATPase activity in HEK293 cells showed reduction by over 20% compared to wild type indicating that this variant impacts protein function (PS3_Supporting; PMID:33375396). 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 1.0.0): PS4, PP3_Moderate, PM3, PM2_Supporting, PS3_Supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.1688 | likely benign ⚠ discordant with ClinVar |
|---|---|---|
| REVEL | 0.852 | moderately pathogenic-leaning |
| SaProt | LLR -9.04 | tolerated |
| ⇒ REVEL calls this damaging; AlphaMissense and SaProt do not. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.6 | GERP 2, phastCons 1 |
| Regional constraint | o/e 0.98 | unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic |
| Overall | ||
| CADD | 28.0 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.00441% | 22,698 |
| European (non-Finnish) | 0.00314% | 31,873 |
| East Asian | 0.00223% | 44,842 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,462 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- ABCA4
- Protein
- p.Arg653Cys
- Coding
- c.1957C>T
- MANE Select
- NM_000350
- dbSNP
- rs61749420
- Type
- single nucleotide variant
- Location
- chr1:94060740 (GRCh38)
- Gene constraint
- LOEUF 0.786 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 75.96 · 8 PDB
- Residue 653
- 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 (in stgd1; likely pathogenic; severely decreased, if any, n-ret-pe-stimulated atpase activity although basal activity is unchanged; decreased n-retinylidene-phosphatidylethanolamine flippase activity; severely decreased n-all-trans-retinylidenephosphatidylethanolamine binding; does not affect solubility; does not affect location in cytoplasmic vesicle); a UniProt-annotated variant site (in stgd1; likely pathogenic; severely decreased n-all-trans-retinylidenephosphatidylethanolamine binding; does not affect solubility; does not affect location in cytoplasmic vesicle; does not affect both basal and n-ret-pe-stimulated atpase activity); a binding site; an α-helix; a disulfide bond
Disease context
ABCA4-related retinopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: retinal disorderage related macular degeneration 2severe early-childhood-onset retinal dystrophyretinitis pigmentosa 19cone-rod dystrophy 3inherited retinal dystrophy
Similar variants
- ABCA4 p.Arg653Leu Likely pathogenic ★★ ⚠ same residue
- ABCA4 p.Arg653fs Pathogenic same residue
- ABCA4 p.Arg653His Pathogenic ★★ ⚠ same residue
- ABCA4 p.Arg653Gly Likely pathogenic ★ same residue
- ABCA4 p.Arg653Ser Pathogenic ★ ⚠ same residue
- ABCA4 c.1937+1G>A Pathogenic ★★★ same condition
- ABCA4 c.3328+2T>A Pathogenic ★★★ same condition
- ABCA4 c.3523-1G>A Pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/abca4-p-arg653cys (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown