Is CRX p.Arg43Ser (c.127C>A) pathogenic?

CRX p.Arg43Ser (c.127C>A) is classified Likely pathogenic in CRX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely pathogenic (0.9998); Very rare (popmax 8.47e-05%, nfe); Associated with cone-rod dystrophy 2.

What condition is associated with CRX p.Arg43Ser (c.127C>A)?

CRX p.Arg43Ser (c.127C>A) is associated with cone-rod dystrophy 2, Leber congenital amaurosis 7 (ClinVar).

How common is CRX p.Arg43Ser (c.127C>A) in the general population?

CRX p.Arg43Ser (c.127C>A) is very rare (popmax 8.47e-05%, nfe) (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 CRX p.Arg43Ser (c.127C>A)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

CRX p.Arg43Ser

c.127C>A · rs1437021651 · VCV1047499

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cone-rod dystrophy 2

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic ✓ concordant with ClinVar · top 3% in CRX
REVEL	0.948	strongly pathogenic-leaning
SaProt	LLR -15.72	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 0.19	GERP -0.72, phastCons 0.56
Regional constraint	o/e 0.89	unconstrained · MANE · 1,933 bp · p 0.26 · regional, not allelic
Overall
CADD	24.1	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 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.84e-05% 1/1,461,866 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: CRX
Protein: p.Arg43Ser
Coding: c.127C>A
MANE Select: NM_000554
dbSNP: rs1437021651
Type: single nucleotide variant
Location: chr19:47836269 (GRCh38)
Gene constraint: LOEUF 0.673 · pLI 0.72 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 61.78 · 1 PDB
Residue 43: a DNA-binding region

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

Disease context

cone-rod dystrophy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Leber congenital amaurosis 7

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

CRX p.Arg43Cys Pathogenic ★★ same residue
CRX p.Arg43His Pathogenic/Likely pathogenic ★★ same residue
CRX p.Arg43Leu Uncertain significance ★ ⚠ same residue
CRX p.Arg43= Likely benign ★ same residue
CRX p.Arg43Pro Likely pathogenic ★ 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

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-arg43ser (accessed [today's date]).

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