ABCA4 p.Ala1598Asp
c.4793C>A · rs61750155 · VCV99321
ClinGen expert panel — ABCA4 VCEP
Pathogenic for ABCA4-related retinopathy. Applied ACMG criteria (verbatim):
PM2_Supporting PS3_Supporting PS4 PM3_Strong PP3 PP4
Curation rationale (ClinGen, verbatim)
The NM_000350.3:c.4793C>A variant is a missense variant predicted to cause this substitution of alanine to aspartic acid at amino acid 1598 (p.Ala1598Asp). The total minor allele frequency in gnomAD v4.1.1 is 0.00002046 (<0.0001) which is lower than the threshold for PM2_Supporting. The computational predictor REVEL gives a score of 0.685 which is in the range of 0.644-0.772, evidence that predicts a damaging effect on ABCA4 function (PP3). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls with an OR of 187.4 and CI of 60.33 to 933.94, 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 three individuals with ABCA4-related retinopathy. At least one patient with this variant displayed presence of at least two ABCA4 variants, onset under 18 years of age, reduced central vision bilaterally and on the presence of “dark choroid” sign of fluorescein angiography, and scotomas, which is highly specific for ABCA4-related retinopathy (PP4, PMID: 27014590). Two were compound heterozygous for the variant and a pathogenic variant and one of those was confirmed in trans by parental testing, and one individual was homozygous for the variant (PM3_Strong; PMIDs: 27014590, 34874912, 41677386). ABCA4 expression and ATPase activity in HEK293 cells showed significant reduction of more than 20% compared to wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 32845050). In summary, this variant meets the criteria to be classified as pathogenic for ABCA4-related retinopathy, specifically when co-occurring with other disease-causing ABCA4 variants, based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP (Specification Version 1.0): PS4, PM3_Strong, PP4, PP3, PS3_Supporting, PM2_Supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.3686 | ambiguous |
|---|---|---|
| REVEL | 0.685 | pathogenic-leaning |
| SaProt | LLR -10.18 | damaging |
| ⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 2.6 | GERP 1, phastCons 0.1 |
| Regional constraint | o/e 0.98 | unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic |
| Overall | ||
| CADD | 15.84 | 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 |
|---|---|---|
| Middle Easterngrpmax | 0.0494% | 2,023 |
| Remaining individualsnot grpmax-eligible | 0.0112% | 8,922 |
| Admixed American | 0.00501% | 19,979 |
| African / African-American | 0.00267% | 37,437 |
| European (non-Finnish) | 0.00153% | 65,529 |
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.Ala1598Asp
- Coding
- c.4793C>A
- MANE Select
- NM_000350
- dbSNP
- rs61750155
- Type
- single nucleotide variant
- Location
- chr1:94021695 (GRCh38)
- Gene constraint
- LOEUF 0.786 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 75.96 · 8 PDB
- Residue 1598
- 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 (in cord3 and stgd1; pathogenic); an α-helix
Disease context
inherited retinal dystrophy — 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 3cone-rod dystrophyretinitis pigmentosaStargardt disease
Similar variants
- ABCA4 p.Ala1598Thr Uncertain significance ★★ ⚠ same residue
- ABCA4 p.Ala1598Ser Uncertain significance ★ same residue
- ABCA4 p.Ala1598= Likely benign ★ same residue
- 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
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-ala1598asp (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown