Is AIPL1 p.Arg302Leu (c.905G>T) pathogenic?

AIPL1 p.Arg302Leu (c.905G>T) is classified Conflicting classifications of pathogenicity in AIPL1 (ClinVar, Conflicting submitters, 16 submitters; last evaluated 2026-04-28). AlphaMissense: likely benign (0.1289); Rare (popmax 0.931%, sas); Associated with Leber congenital amaurosis 1.

What condition is associated with AIPL1 p.Arg302Leu (c.905G>T)?

AIPL1 p.Arg302Leu (c.905G>T) is associated with Leber congenital amaurosis 1, pathologic nystagmus, Leber congenital amaurosis 4 (ClinVar).

How common is AIPL1 p.Arg302Leu (c.905G>T) in the general population?

AIPL1 p.Arg302Leu (c.905G>T) is rare (popmax 0.931%, sas) (gnomAD).

How is Leber congenital amaurosis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about AIPL1 p.Arg302Leu (c.905G>T)?

AlphaMissense predicts likely benign (score 0.1289) — an in-silico prediction, not a clinical call.

AIPL1 p.Arg302Leu

c.905G>T · rs62637015 · VCV65712

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.1289 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.931%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Leber congenital amaurosis 1

Computational evidence

Protein change
AlphaMissense	0.1289	likely benign
REVEL	0.406	indeterminate
SaProt	LLR -6.49	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -4.5
Regional constraint	o/e 0.96	unconstrained · MANE · 9,641 bp · p 0.35 · regional, not allelic
Overall
CADD	13.98	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.931% South Asian · 848/91,080 alleles

Filtering AF 0.879% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.858%

Overall 0.155% 2,496/1,608,168 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.931%	107
Middle Eastern	0.875%	114
Ashkenazi Jewishnot grpmax-eligible	0.561%	178
Admixed American	0.378%	264
Remaining individualsnot grpmax-eligible	0.263%	381
European (non-Finnish)	0.0868%	1,152
African / African-American	0.016%	6,254
East Asian	0.00223%	44,874
Finnishnot grpmax-eligible	0.00172%	58,114

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.Arg302Leu
Coding: c.905G>T
MANE Select: NM_014336
dbSNP: rs62637015
Type: single nucleotide variant
Location: chr17:6425710 (GRCh38)
Gene constraint: LOEUF 1.01 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.42 · 6 PDB
Residue 302: a UniProt-annotated variant site (found in a patient with lca4; there is no interaction with nub1); an α-helix

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

Disease context

Leber congenital amaurosis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pathologic nystagmus Leber congenital amaurosis 4 myopia 25, autosomal dominant

For Leber congenital amaurosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

AIPL1 p.Arg302fs Pathogenic ★ 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
AIPL1 p.Asp51Gly Likely pathogenic ★★★ same condition
AIPL1 p.Cys239Arg Likely 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-arg302leu (accessed [today's date]).

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