ABCA4 p.Trp663Ter
c.1988G>A · rs865990202 · VCV372289
ClinGen expert panel — ABCA4 VCEP
Pathogenic for ABCA4-related retinopathy. Applied ACMG criteria (verbatim):
PVS1 PM2_Supporting PS4
Curation rationale (ClinGen, verbatim)
The NM_000350.3:c.1988G>A (p.Trp663Ter) variant in ABCA4 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 14/50 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 v4.1.1 is 0.000001239 (2/1614018 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001). This variant has been observed in individuals with Stargardt disease and retinal dystrophy (PMID: 25640233, 27353947, 29848554). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls with an OR of Infinity and CI of 42.77 to Infinity, which is above the ABCA4 VCEP threshold of ≥5, where the CI does not contain 1 (PS4; PMID: 35120629). 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 (v.1.0.0): PVS1, PS4, PM2_Supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Consequence | nonsense (stop-gain) | predicted loss-of-function |
|---|---|---|
| NMD | predicted | premature termination codon in exon 14 of 50 |
| Splicing | ||
| SpliceAI | Δ0.37 | acceptor gain · deltas |
| Pangolin | Δ0.25 | gain · loss 0.10 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 7.7 | GERP 2, phastCons 1 |
| Overall | ||
| CADD | 44.0 | PHRED · no single calibrated threshold — expert panels disagree |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
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.Trp663Ter
- Coding
- c.1988G>A
- MANE Select
- NM_000350
- dbSNP
- rs865990202
- Type
- single nucleotide variant
- Location
- chr1:94060709 (GRCh38)
- Gene constraint
- LOEUF 0.786 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 75.96 · 8 PDB
- Residue 663
- 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); an α-helix; a disulfide bond
Similar variants
- ABCA4 c.1937+1G>A Pathogenic ★★★ same condition
- ABCA4 c.3523-1G>A Pathogenic ★★★ same condition
- ABCA4 c.4253+43G>A Pathogenic ★★★ same condition
- ABCA4 c.4254-1G>C Pathogenic ★★★ same condition
- ABCA4 c.4352+1G>A Pathogenic ★★★ same condition
- ABCA4 c.4773+3A>G Pathogenic ★★★ same condition
- ABCA4 c.5018+2T>A Pathogenic ★★★ same condition
- ABCA4 c.5018+2T>C 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-trp663ter (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown