ClinGen expert panel — ABCA4 VCEP
Benign for ABCA4-related retinopathy. Applied ACMG criteria (verbatim):
BP7_Moderate BA1
Curation rationale (ClinGen, verbatim)
The NM_000350.3(ABCA4):c.6285T>C variant is a synonymous variant, p.Asp2095=. The GroupMax filtering allele frequency in gnomAD v4.1.0 is 0.6547, which is greater than the ClinGen ABCA4 VCEP’s threshold for BA1 (>0.163). The computational splicing predictor SpliceAI gives this synonymous variant a delta score of 0.03 for donor gain, which is below the ClinGen ABCA4 VCEP BP7 threshold of <0.1 and does not strongly predict a splicing defect (BP7_Moderate). In summary, this variant meets the criteria to be classified as benign for ABCA4-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP (Specification Version 1.0.0): BA1, BP7_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. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · A>T here scores Δ0.49 · evaluated, not missing |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -0.3 | GERP -1.7, phastCons 0.001 |
| Overall | ||
| CADD | 0.305 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 66% | 2 |
| Middle Eastern | 23.9% | 4 |
| Amishnot grpmax-eligible | 23% | 4 |
| Ashkenazi Jewishnot grpmax-eligible | 19.4% | 5 |
| Remaining individualsnot grpmax-eligible | 16.7% | 6 |
| South Asian | 16.6% | 6 |
| East Asian | 14.5% | 7 |
| Admixed American | 11.6% | 9 |
| European (non-Finnish) | 11.4% | 9 |
| Finnishnot grpmax-eligible | 7.49% | 13 |
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.Asp2095=
- Coding
- c.6285T>C
- MANE Select
- NM_000350
- dbSNP
- rs1801555
- Type
- single nucleotide variant
- Location
- chr1:94001103 (GRCh38)
- Gene constraint
- LOEUF 0.786 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 75.96 · 8 PDB
- Residue 2095
- 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 β-strand
Similar variants
- ABCA4 p.Asp2095Val Likely pathogenic ★★ same residue
- ABCA4 p.Asp2095Tyr Likely 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
- ABCA4 c.4253+43G>A Pathogenic ★★★ same condition
- ABCA4 c.4254-1G>C Pathogenic ★★★ same condition
- ABCA4 c.4352+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-asp2095 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown