AIPL1 p.Arg102Trp
c.304C>T · rs151204387 · VCV1385342
ClinGen expert panel — Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP
Uncertain Significance for AIPL1-related retinopathy. Applied ACMG criteria (verbatim):
PM2_Supporting PP3
Curation rationale (ClinGen, verbatim)
NM_014336.5(AIPL1):c.304C>T (p.Arg102Trp) is a missense variant replacing the arginine at position p.102 with tryptophan. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000021, with 34 alleles / 1613846 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.687, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on AIPL1 protein function (PP3). In summary, this variant meets the criteria to be classified as a VUS for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting and PP3. (VCEP specifications version 1.0.0; date of approval 09/24/2025).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.3922 | ambiguous |
|---|---|---|
| REVEL | 0.687 | pathogenic-leaning |
| SaProt | LLR -12.39 | damaging |
| ⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · G>T here scores Δ0.42 · evaluated, not missing |
| Constraint at this position | ||
| Conservation | phyloP 2.6 | GERP -2.2, phastCons 1 |
| Regional constraint | o/e 0.96 | unconstrained · MANE · 9,641 bp · p 0.35 · regional, not allelic |
| Overall | ||
| CADD | 25.5 | 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 |
|---|---|---|
| African / African-Americangrpmax | 0.0174% | 5,764 |
| East Asian | 0.00223% | 44,876 |
| Admixed American | 0.00167% | 60,008 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,484 |
| European (non-Finnish) | 0.00153% | 65,557 |
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
- AIPL1
- Protein
- p.Arg102Trp
- Coding
- c.304C>T
- MANE Select
- NM_014336
- dbSNP
- rs151204387
- Type
- single nucleotide variant
- Location
- chr17:6428479 (GRCh38)
- Gene constraint
- LOEUF 1.01 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 83.42 · 6 PDB
- Residue 102
- the ppiase fkbp-type domain; an α-helix
Similar variants
- AIPL1 p.Arg102Gln Uncertain significance ★★ ⚠ same residue
- AIPL1 p.Arg102Gly Uncertain significance ★ ⚠ same residue
- AIPL1 p.Arg102= Likely benign ★ same residue
- AIPL1 c.276+1G>A Pathogenic ★★★ same condition
- AIPL1 c.277-2A>G Pathogenic ★★★ same condition
- AIPL1 p.Ala197Pro Pathogenic ★★★ same condition
- AIPL1 p.Arg270His Pathogenic ★★★ same condition
- AIPL1 p.Arg32Ter 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/aipl1-p-arg102trp (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown