ABCA4 p.Arg2139Pro
c.6416G>C · rs761867791 · VCV298222
ClinGen expert panel — ABCA4 VCEP
Pathogenic for ABCA4-related retinopathy. Applied ACMG criteria (verbatim):
PP3_Moderate PM2_Supporting PS4 PP1 PM3 PM5
Curation rationale (ClinGen, verbatim)
The NM_000350.3(ABCA4):c.6416G>C variant in ABCA4 is a missense variant predicted to cause substitution of arginine by proline at amino acid 2139 (p.Arg2139Pro). The total minor allele frequency in gnomAD v4.1.0 is 0.000006195 (10/1614076 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001). The computational predictor REVEL gives a score of 0.997 which is above the threshold of >0.772, evidence that predicts a damaging effect on ABCA4 function (PP3_Moderate). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls with an OR is infinity and the CI is 2.24-infinity, 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 1 individual with ABCA4-related retinopathy who was compound heterozygous for the variant and a pathogenic variant (c.2588G>C; p.Gly863Ala) which was confirmed in trans by parental/family testing (PMID: 28559085; PM3). The variant has been reported to segregate with ABCA4-related retinopathy in the proband and 1 similarly affected relative (PP1; PMID: 25472526). Another missense variant, c.6415C>T (p.Arg2139Trp), in the same codon has been classified as pathogenic for ABCA4-related retinopathy by the ClinGen ABCA4 VCEP, and Splice AI revealed no expected effects on splicing (PM5). 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): PS4, PM3, PP1, PM2_Supporting, PP3_Moderate, PM5.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9909 | likely pathogenic ✓ concordant with ClinVar · top 1% in ABCA4 |
|---|---|---|
| REVEL | 0.997 | strongly pathogenic-leaning |
| SaProt | LLR -15.89 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 3.9 | GERP 1.8, phastCons 1 |
| Regional constraint | o/e 0.98 | unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic |
| Overall | ||
| CADD | 30.0 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
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.Arg2139Pro
- Coding
- c.6416G>C
- MANE Select
- NM_000350
- dbSNP
- rs761867791
- Type
- single nucleotide variant
- Location
- chr1:94000899 (GRCh38)
- Gene constraint
- LOEUF 0.786 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 75.96 · 8 PDB
- Residue 2139
- 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 UniProt-annotated variant site (in stgd1); a β-strand
Similar variants
- ABCA4 p.Arg2139Gln Likely pathogenic ★★★ ⚠ same residue
- ABCA4 p.Arg2139Trp 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-arg2139pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown