ABCA4 p.Ser1642fs
c.4924_4927del · VCV3381789
ClinGen expert panel — ABCA4 VCEP
Pathogenic for ABCA4-related retinopathy. Applied ACMG criteria (verbatim):
PVS1 PM3_Supporting PM2_Supporting PP1_Moderate
Curation rationale (ClinGen, verbatim)
The NM_000350.3:c.4924_4927del (p.Ser1642fs) variant in ABCA4 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 35/50 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 0.000001239 (2/1614206 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 not significantly increased compared with the prevalence in controls with an OR of infinity and the CI is 0.31-infinity, which is above the ABCA4 VCEP threshold of ≥5, but the CI does contain 1 (PMID: 35120629). This variant has been detected in at least 1 individual with ABCA4-related retinopathy who was homozygous for the variant (PM3_Supporting; ClinVar SCV: SCV005415477.1). The variant has been reported to segregate with ABCA4-related retinopathy in the proband and 2 similarly affected relatives (PP1_Moderate; ClinVar SCV: SCV005415477.1). 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): PVS1, PM3_Supporting, PM2_Supporting, PP1_Moderate.
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 carries the signal. | ||
| Consequence | frameshift | predicted loss-of-function |
|---|---|---|
| NMD | predicted | premature termination codon in exon 35 of 50 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 11 | GERP 2, phastCons 1 |
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.Ser1642fs
- Coding
- c.4924_4927del
- MANE Select
- NM_000350
- Type
- Deletion
- Location
- chr1:94021331 (GRCh38)
- Gene constraint
- LOEUF 0.786 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 75.96 · 8 PDB
- Residue 1642
- 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); a UniProt-annotated variant site (in stgd1 and cord3; uncertain significance); a UniProt-annotated variant site (sequence variant)
Similar variants
- ABCA4 p.Ala960fs Pathogenic ★★★ same condition
- ABCA4 p.Asp279fs Pathogenic ★★★ same condition
- ABCA4 p.Gly1972_Val1973insTer Pathogenic ★★★ same condition
- ABCA4 p.Gly963fs Pathogenic ★★★ same condition
- ABCA4 p.Leu1741fs Pathogenic ★★★ same condition
- ABCA4 p.Leu296fs Pathogenic ★★★ same condition
- ABCA4 p.Lys1033fs Pathogenic ★★★ same condition
- ABCA4 p.Thr1519fs 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-ser1642fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown