ABCA4 p.Ala1773Val
c.5318C>T · rs760549861 · VCV236129
ClinGen expert panel — ABCA4 VCEP
Pathogenic for ABCA4-related retinopathy. Applied ACMG criteria (verbatim):
PP3_Moderate PM2_Supporting PS4 PM3_Strong PP1
Curation rationale (ClinGen, verbatim)
The NM_000350.3(ABCA4):c.5318C>T is a missense variant predicted to cause substitution of alanine by valine at amino acid 1773 (p.Ala1773Val). Minor allele frequency in gnomAD v4.1.0 is 0.0000254 (41/1613990 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001). The computational predictor REVEL gives a score of 0.79 which is above the threshold of >0.772 meeting PP3_Moderate. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls with an OR of 138.9 and CI of 56.18 to 447.50, which is above the ABCA4 VCEP threshold of >3, where the CI does not contain 1 (PS4; PMID: 35120629). This variant has been detected in at least ten individuals with ABCA4-related retinopathy. Of those individuals, one was compound heterozygous for the variant and a pathogenic variant, confirmed in trans by family testing. In addition, this variant has been detected in at least nine individuals with ABCA4-related retinopathy and who were homozygous for the variant, which may represent a founder variant in Mexico (PM3_Strong, PMID: 29422768, 37774808). The variant has been reported to segregate with ABCA4-related retinopathy in one proband and 1 similarly affected relative (PP1; PMID: 29422768). 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, PM3_Strong, PP3_Moderate, PP1, PM2_supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.7913 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.79 | moderately pathogenic-leaning |
| SaProt | LLR -10.18 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · G>C here scores Δ0.21 · evaluated, not missing |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 1.7, phastCons 1 |
| Regional constraint | o/e 0.98 | unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic |
| Overall | ||
| CADD | 31.0 | 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 |
|---|---|---|
| Admixed Americangrpmax | 0.0267% | 3,751 |
| East Asian | 0.00445% | 22,449 |
| South Asian | 0.00439% | 22,769 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00338% | 29,602 |
| Remaining individualsnot grpmax-eligible | 0.0032% | 31,240 |
| Finnishnot grpmax-eligible | 0.00156% | 64,018 |
| European (non-Finnish) | 0.00127% | 78,669 |
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.Ala1773Val
- Coding
- c.5318C>T
- MANE Select
- NM_000350
- dbSNP
- rs760549861
- Type
- single nucleotide variant
- Location
- chr1:94014685 (GRCh38)
- Gene constraint
- LOEUF 0.786 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 75.96 · 8 PDB
- Residue 1773
- 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); a UniProt-annotated variant site (in stgd1 and ffm; uncertain significance); a UniProt-annotated variant site (found in a patient with chorioretinal atrophy; likely pathogenic; severely decreases solubility; loss of cytoplasmic vesicle localization; decreased basal atpase activity to 30-50% and n-ret-pe-induced activity to 20% of wild-type values; decreased n-all-trans-retinylidenephosphatidylethanolamine binding); a UniProt-annotated variant site (in stgd1; likely pathogenic; severely decreases solubility; loss of cytoplasmic vesicle localization; decreases basal and n-ret-pe-induced atpase activity to less than 30% of wild-type values; decreased n-all-trans-retinylidenephosphatidylethanolamine binding); an α-helix
Disease context
ABCA4-related retinopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: age related macular degeneration 2severe early-childhood-onset retinal dystrophyretinitis pigmentosa 19cone-rod dystrophy 3inherited retinal dystrophyStargardt disease
Similar variants
- ABCA4 p.Ala1773Glu Pathogenic/Likely pathogenic ★★ same residue
- ABCA4 p.Ala1773= Likely benign ★★ 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-ala1773val (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown