AIPL1 p.Val12fs
c.34dup · rs752193525 · VCV813151
ClinGen expert panel — Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP
Likely Pathogenic for AIPL1-related retinopathy. Applied ACMG criteria (verbatim):
PVS1 PM2_Supporting
Curation rationale (ClinGen, verbatim)
NM_014336.5(AIPL1):c.34dup (p.Val12GlyfsTer?) is a 1 bp duplication that changes amino acid p.12 from valine to glycine and alters the reading frame, with a new stop codon encountered after 32 amino acids. This premature stop codon in exon 1 of 6 is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000001859, with 3 /1614036 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state (PMID: 32531858). However, the proband was not counted for PM3_Supporting because the other variant p.Arg80Trp is currently classified as a VUS and was not confirmed to be in trans. In summary, this variant meets the criteria to be classified as Likely Pathogenic for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1 and PM2_supporting. (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 | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | frameshift | predicted loss-of-function |
|---|---|---|
| NMD | predicted | premature termination codon in exon 1 of 6 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 9.2 | GERP 1.9, phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
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
- AIPL1
- Protein
- p.Val12fs
- Coding
- c.34dup
- MANE Select
- NM_014336
- dbSNP
- rs752193525
- Type
- Duplication
- Location
- chr17:6435070 (GRCh38)
- Gene constraint
- LOEUF 1.01 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 83.42 · 6 PDB
- Residue 12
- a β-strand
Similar variants
- AIPL1 p.Cys207fs Pathogenic ★★★ same condition
- AIPL1 p.Ala352_Pro355dup Uncertain significance ★★★ same condition
- AIPL1 p.Glu318fs Pathogenic/Likely pathogenic ★★ same condition
- AIPL1 p.Lys200fs Pathogenic ★★ same condition
- AIPL1 p.Phe35delinsLeuTer Pathogenic ★★ same condition
- AIPL1 p.Asn171fs Pathogenic ★ same condition
- AIPL1 p.His260fs Pathogenic ★ same condition
- AIPL1 p.His60fs 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-val12fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown