Is CRX p.Arg90Gln (c.269G>A) pathogenic?

CRX p.Arg90Gln (c.269G>A) is classified Conflicting classifications of pathogenicity in CRX (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-23). AlphaMissense: likely pathogenic (0.9893); Very rare (popmax 0.00167%, amr); Associated with CRX-related disorders.

What condition is associated with CRX p.Arg90Gln (c.269G>A)?

CRX p.Arg90Gln (c.269G>A) is associated with CRX-related disorders, cone-rod dystrophy 2, Leber congenital amaurosis 7 (ClinVar).

How common is CRX p.Arg90Gln (c.269G>A) in the general population?

CRX p.Arg90Gln (c.269G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CRX p.Arg90Gln (c.269G>A)?

AlphaMissense predicts likely pathogenic (score 0.9893) — an in-silico prediction, not a clinical call.

CRX p.Arg90Gln

c.269G>A · rs1209634994 · VCV452003

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CRX-related disorders

Computational evidence

Protein change
AlphaMissense	0.9893	likely pathogenic · top 10% in CRX
REVEL	0.901	moderately pathogenic-leaning
SaProt	LLR -11.33	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 7.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.18	constrained · MANE · 2,963 bp · p 0.00074 · regional, not allelic
Overall
CADD	31.0	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 0.00167% Admixed American · 1/59,954 alleles

Filtering AF 0.000954% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00136% 22/1,613,228 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,560
Admixed Americangrpmax	0.00167%	59,954
Finnishnot grpmax-eligible	0.00157%	63,886
European (non-Finnish)	0.00153%	65,542
South Asian	0.0011%	91,044

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg90Gln
Coding: c.269G>A
MANE Select: NM_000554
dbSNP: rs1209634994
Type: single nucleotide variant
Location: chr19:47839336 (GRCh38)
Gene constraint: LOEUF 0.673 · pLI 0.72 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 61.78 · 1 PDB
Residue 90: a DNA-binding region; a UniProt-annotated variant site (in lca7; reduced dna-binding ability, transcriptional synergy and interaction with nrl); an α-helix

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

Disease context

CRX-related disorders

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

Similar variants

CRX p.Arg90Trp Pathogenic/Likely pathogenic ★★ same residue
CRX p.Arg90= Likely benign ★ 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

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-arg90gln (accessed [today's date]).

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