Is AIPL1 p.Glu86Lys (c.256G>A) pathogenic?

AIPL1 p.Glu86Lys (c.256G>A) is classified Uncertain significance in AIPL1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-23). AlphaMissense: ambiguous (0.4149); Ultra-rare (popmax 0.0166%, mid); Associated with Leber congenital amaurosis 4.

What condition is associated with AIPL1 p.Glu86Lys (c.256G>A)?

AIPL1 p.Glu86Lys (c.256G>A) is associated with Leber congenital amaurosis 4 (ClinVar).

How common is AIPL1 p.Glu86Lys (c.256G>A) in the general population?

AIPL1 p.Glu86Lys (c.256G>A) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

How is Cone rod dystrophy 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.Glu86Lys (c.256G>A)?

AlphaMissense predicts ambiguous (score 0.4149) — an in-silico prediction, not a clinical call.

AIPL1 p.Glu86Lys

c.256G>A · rs549595673 · VCV2052493

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4149 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Leber congenital amaurosis 4

Computational evidence

Protein change
AlphaMissense	0.4149	ambiguous
REVEL	0.766	pathogenic-leaning
SaProt	LLR -11.82	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 9,641 bp · p 0.35 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,024 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.00186% 30/1,613,936 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,024
South Asian	0.0132%	7,586
Remaining individualsnot grpmax-eligible	0.008%	12,498
African / African-American	0.00666%	15,009
East Asian	0.00446%	22,422
European (non-Finnish)	0.000424%	235,991

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.Glu86Lys
Coding: c.256G>A
MANE Select: NM_014336
dbSNP: rs549595673
Type: single nucleotide variant
Location: chr17:6433939 (GRCh38)
Gene constraint: LOEUF 1.01 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.42 · 6 PDB
Residue 86: the ppiase fkbp-type domain; a β-strand

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

Disease context

Leber congenital amaurosis 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Cone rod dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

AIPL1 p.Glu86Gln Uncertain significance ★★ ⚠ 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-glu86lys (accessed [today's date]).

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