Is CRX p.Leu299Phe (c.897G>C) pathogenic?

CRX p.Leu299Phe (c.897G>C) is classified Conflicting classifications of pathogenicity in CRX (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-07-12). AlphaMissense: likely pathogenic (0.7347); Ultra-rare (popmax 0.0178%, eas); Associated with inherited retinal dystrophy.

What condition is associated with CRX p.Leu299Phe (c.897G>C)?

CRX p.Leu299Phe (c.897G>C) is associated with inherited retinal dystrophy, cone-rod dystrophy 2, Leber congenital amaurosis 7 (ClinVar).

How common is CRX p.Leu299Phe (c.897G>C) in the general population?

CRX p.Leu299Phe (c.897G>C) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about CRX p.Leu299Phe (c.897G>C)?

AlphaMissense predicts likely pathogenic (score 0.7347) — an in-silico prediction, not a clinical call.

CRX p.Leu299Phe

c.897G>C · rs527236063 · VCV143086

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7347 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.7347	likely pathogenic
REVEL	0.748	pathogenic-leaning
SaProt	LLR -8.87	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.52, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 622 bp · p 0.35 · regional, not allelic
Overall
CADD	23.3	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 0.0178% East Asian · 8/44,876 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000548% 8/1,460,998 alleles · ultra-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: CRX
Protein: p.Leu299Phe
Coding: c.897G>C
MANE Select: NM_000554
dbSNP: rs527236063
Type: single nucleotide variant
Location: chr19:47839964 (GRCh38)
Gene constraint: LOEUF 0.673 · pLI 0.72 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 61.78 · 1 PDB

Full CRX 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

Also linked: cone-rod dystrophy 2 Leber congenital amaurosis 7 retinitis pigmentosa

Similar variants

CRX p.Leu299Val Uncertain significance ★ same residue
CRX c.101-1G>A Pathogenic/Likely pathogenic ★★ same condition
CRX p.Arg40Gln Pathogenic/Likely pathogenic ★★ same condition
CRX p.Arg40Trp Pathogenic/Likely pathogenic ★★ same condition
CRX p.Arg41Gln Pathogenic/Likely pathogenic ★★ same condition
CRX p.Arg41Pro Likely pathogenic ★★ same condition
CRX p.Arg43Cys Pathogenic ★★ same condition
CRX p.Arg43His Pathogenic/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/crx-p-leu299phe (accessed [today's date]).

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