Is AIPL1 p.Arg258Pro (c.773G>C) pathogenic?

AIPL1 p.Arg258Pro (c.773G>C) is classified Pathogenic in AIPL1 (ClinVar, Single submitter, 3 submitters; last evaluated 2023-07-17). AlphaMissense: likely pathogenic (0.8486); Very rare (popmax 0.00446%, eas); Associated with Leber congenital amaurosis 4.

What condition is associated with AIPL1 p.Arg258Pro (c.773G>C)?

AIPL1 p.Arg258Pro (c.773G>C) is associated with Leber congenital amaurosis 4 (ClinVar).

How common is AIPL1 p.Arg258Pro (c.773G>C) in the general population?

AIPL1 p.Arg258Pro (c.773G>C) is very rare (popmax 0.00446%, eas) (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.Arg258Pro (c.773G>C)?

AlphaMissense predicts likely pathogenic (score 0.8486) — an in-silico prediction, not a clinical call.

AIPL1 p.Arg258Pro

c.773G>C · rs751881283 · VCV916626

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8486 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Leber congenital amaurosis 4

Computational evidence

Protein change
AlphaMissense	0.8486	likely pathogenic ✓ concordant with ClinVar
REVEL	0.767	pathogenic-leaning
SaProt	LLR -11.69	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.20	donor gain · deltas
Constraint at this position
Conservation	phyloP 0.21	GERP 0.005
Regional constraint	o/e 0.96	unconstrained · MANE · 9,641 bp · p 0.35 · regional, not allelic
Overall
CADD	22.0	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 0.00446% East Asian · 2/44,876 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000616% 9/1,461,640 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,438
South Asian	0.0022%	45,539
European (non-Finnish)	0.000424%	235,997

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.Arg258Pro
Coding: c.773G>C
MANE Select: NM_014336
dbSNP: rs751881283
Type: single nucleotide variant
Location: chr17:6426626 (GRCh38)
Gene constraint: LOEUF 1.01 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.42 · 6 PDB
Residue 258: an α-helix

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.Arg258Gly Uncertain significance ★ ⚠ same residue
AIPL1 p.Arg258Trp Uncertain significance ★ ⚠ same residue
AIPL1 p.Arg258= Likely benign ★ same residue
AIPL1 p.Arg258Gln 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

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-arg258pro (accessed [today's date]).

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