Is AIPL1 p.Lys243del (c.724AAG[1]) pathogenic?

AIPL1 p.Lys243del (c.724AAG[1]) is classified Likely pathogenic in AIPL1 (ClinVar, Expert panel, 3 submitters; last evaluated 2025-09-29). Very rare (popmax 0.00153%, nfe); Associated with AIPL1-related retinopathy.

What condition is associated with AIPL1 p.Lys243del (c.724AAG[1])?

AIPL1 p.Lys243del (c.724AAG[1]) is associated with AIPL1-related retinopathy, Leber congenital amaurosis 4 (ClinVar).

How common is AIPL1 p.Lys243del (c.724AAG[1]) in the general population?

AIPL1 p.Lys243del (c.724AAG[1]) is very rare (popmax 0.00153%, nfe) (gnomAD).

AIPL1 p.Lys243del

c.724AAG[1] · rs765411357 · VCV1419404

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Conditions

AIPL1-related retinopathy

ClinGen expert panel — Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

Likely Pathogenic for AIPL1-related retinopathy. Applied ACMG criteria (verbatim):

PM2_Supporting PM3_Strong PM4_Supporting PP4

Curation rationale (ClinGen, verbatim)

NM_014336.5(AIPL1):c.727_729del (p.Lys243del) is an in-frame deletion of three nucleotides predicted to cause a change in the length of the protein due to deletion of 1 amino acid in a non-repeat region, with at least one of the deleted base pairs highly conserved with a PhyloP conservation score of 2.5 (PM4_Supporting). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.00001115, with 18 / 1,614,218 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 was homozygous for the variant (0.5 points, VCEP member-provided data). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_014336.5(AIPL1):c.834G>A (p.Trp278Ter) variant suspected in trans (0.5 points, PMID: 32865313), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP, or the NM_014336.5(AIPL1):c.190G>A (p.Gly64Arg) variant confirmed in trans (1 point, VCEP member-provided data, Blueprint Genetics), which was previously classified likely pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). A fourth proband with retinal dystrophy has been reported harboring the variant in the compound heterozygous state with the NM_014336.5(AIPL1):c.364G>A (p.Gly122Arg) variant, however, additional information will be required for inclusion in PM3 (VCEP member-provided data). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts) with light-seeking behavior (1 pt) from birth (1 pt), nystagmus (1 pt), central visual acuity limited to light perception (1 pt), and relatively normal fundus appearance at age 1 year with very mild granular RPE pigmentation (0.5 pts), which together are specific for AIPL1-related retinopathy (total 4 points, PMID: 32865313, PP4). 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: PM4_Supporting, PM2_Supporting, PM3_Strong, and PP4. (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.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.9	GERP 1.1, phastCons 0.24

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00153% European (non-Finnish) · 18/1,180,044 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00123% 18/1,461,852 alleles · very rare

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.Lys243del
Coding: c.724AAG[1]
MANE Select: NM_014336
dbSNP: rs765411357
Type: Microsatellite
Location: chr17:6426670 (GRCh38)
Gene constraint: LOEUF 1.01 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.42 · 6 PDB

Full AIPL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: Leber congenital amaurosis 4

Similar variants

AIPL1 p.Lys243= Likely benign ★ same residue
AIPL1 p.Glu337fs Pathogenic ★★★ same condition
AIPL1 p.Arg302fs Pathogenic ★ same condition
AIPL1 c.276+1G>A Pathogenic ★★★ same condition
AIPL1 c.276+2T>C Pathogenic ★★★ same condition
AIPL1 c.277-2A>G Pathogenic ★★★ same condition
AIPL1 p.Ala197Pro Pathogenic ★★★ same condition
AIPL1 p.Arg270His 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-lys243del (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown