Is AIPL1 p.Arg258Gln (c.773G>A) pathogenic?

AIPL1 p.Arg258Gln (c.773G>A) is classified Likely benign in AIPL1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-01-06). AlphaMissense: likely benign (0.0694); Ultra-rare (popmax 0.0747%, sas); Associated with Leber congenital amaurosis 4.

What condition is associated with AIPL1 p.Arg258Gln (c.773G>A)?

AIPL1 p.Arg258Gln (c.773G>A) is associated with Leber congenital amaurosis 4, Fraser syndrome 3 (ClinVar).

How common is AIPL1 p.Arg258Gln (c.773G>A) in the general population?

AIPL1 p.Arg258Gln (c.773G>A) is ultra-rare (popmax 0.0747%, sas) (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.Arg258Gln (c.773G>A)?

AlphaMissense predicts likely benign (score 0.0694) — an in-silico prediction, not a clinical call.

AIPL1 p.Arg258Gln

c.773G>A · rs751881283 · VCV974702

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0694 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0747%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Leber congenital amaurosis 4

Computational evidence

Protein change
AlphaMissense	0.0694	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -6.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.20 · evaluated, not missing
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	15.22	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 0.0747% South Asian · 68/91,082 alleles

Filtering AF 0.0604% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0552%

Overall 0.00514% 83/1,613,862 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0747%	1,339
Remaining individualsnot grpmax-eligible	0.0064%	15,622
African / African-American	0.00133%	74,934
European (non-Finnish)	0.000847%	117,999

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.Arg258Gln
Coding: c.773G>A
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

Also linked: Fraser syndrome 3

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.Arg258Pro Pathogenic ★ same residue
AIPL1 p.Arg258Gly Uncertain significance ★ ⚠ same residue
AIPL1 p.Arg258Trp Uncertain significance ★ ⚠ same residue
AIPL1 p.Arg258= 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-arg258gln (accessed [today's date]).

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