Is CRX p.Arg40Pro (c.119G>C) pathogenic?

CRX p.Arg40Pro (c.119G>C) is classified Uncertain significance in CRX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-12). AlphaMissense: likely pathogenic (0.9892); Absent from gnomAD v4.1; Associated with Leber congenital amaurosis 7.

What condition is associated with CRX p.Arg40Pro (c.119G>C)?

CRX p.Arg40Pro (c.119G>C) is associated with Leber congenital amaurosis 7, cone-rod dystrophy 2 (ClinVar).

How common is CRX p.Arg40Pro (c.119G>C) in the general population?

CRX p.Arg40Pro (c.119G>C) is absent from gnomAD v4.1 (gnomAD).

How is Leber congenital amaurosis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CRX p.Arg40Pro (c.119G>C)?

AlphaMissense predicts likely pathogenic (score 0.9892) — an in-silico prediction, not a clinical call.

CRX p.Arg40Pro

c.119G>C · rs771450991 · VCV2037356

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9892 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Leber congenital amaurosis 7

Computational evidence

Protein change
AlphaMissense	0.9892	likely pathogenic · top 10% in CRX
REVEL	0.972	strongly pathogenic-leaning
SaProt	LLR -15.62	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 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,933 bp · p 0.26 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CRX
Protein: p.Arg40Pro
Coding: c.119G>C
MANE Select: NM_000554
dbSNP: rs771450991
Type: single nucleotide variant
Location: chr19:47836261 (GRCh38)
Gene constraint: LOEUF 0.673 · pLI 0.72 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 61.78 · 1 PDB
Residue 40: a DNA-binding region

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

Disease context

Leber congenital amaurosis 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cone-rod dystrophy 2

For Leber congenital amaurosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CRX p.Arg40Gln Pathogenic/Likely pathogenic ★★ same residue
CRX p.Arg40Trp Pathogenic/Likely pathogenic ★★ same residue
CRX p.Arg40Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CRX c.101-1G>A Pathogenic/Likely pathogenic ★★ same condition
CRX p.Arg41Gln Pathogenic/Likely pathogenic ★★ same condition
CRX p.Arg43Cys Pathogenic ★★ same condition
CRX p.Arg43His Pathogenic/Likely pathogenic ★★ same condition
CRX p.Arg69Cys 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-arg40pro (accessed [today's date]).

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