Is AIPL1 p.Trp222Arg (c.664T>C) pathogenic?

AIPL1 p.Trp222Arg (c.664T>C) is classified Likely pathogenic in AIPL1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2017-01-01). AlphaMissense: likely pathogenic (0.9894); Very rare (popmax 0.000339%, nfe); Associated with inherited retinal dystrophy.

What condition is associated with AIPL1 p.Trp222Arg (c.664T>C)?

AIPL1 p.Trp222Arg (c.664T>C) is associated with inherited retinal dystrophy (ClinVar).

How common is AIPL1 p.Trp222Arg (c.664T>C) in the general population?

AIPL1 p.Trp222Arg (c.664T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about AIPL1 p.Trp222Arg (c.664T>C)?

AlphaMissense predicts likely pathogenic (score 0.9894) — an in-silico prediction, not a clinical call.

AIPL1 p.Trp222Arg

c.664T>C · VCV3250217

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9894 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.9894	likely pathogenic ✓ concordant with ClinVar · top 3% in AIPL1
REVEL	0.666	pathogenic-leaning
SaProt	LLR -11.45	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 9,641 bp · p 0.35 · regional, not allelic
Overall
CADD	28.1	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 0.000339% European (non-Finnish) · 4/1,179,954 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,854 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.Trp222Arg
Coding: c.664T>C
MANE Select: NM_014336
Type: single nucleotide variant
Location: chr17:6426735 (GRCh38)
Gene constraint: LOEUF 1.01 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.42 · 6 PDB
Residue 222: an α-helix

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AIPL1 p.Trp222Ter Pathogenic same residue
AIPL1 p.Trp278Ter Pathogenic ★★★ same condition
AIPL1 p.Ala336Thr Benign ★★★ same condition
AIPL1 p.Arg324Leu Benign ★★★ same condition
AIPL1 p.Pro376Ser Benign ★★★ same condition
AIPL1 p.Thr114Ile Benign ★★★ ⚠ same condition
AIPL1 p.Gln155His Pathogenic/Likely pathogenic ★★ ⚠ same condition
AIPL1 p.Arg80Gln Uncertain significance ★★ ⚠ 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-trp222arg (accessed [today's date]).

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