Is CRB1 p.Arg744= (c.2230C>A) pathogenic?

CRB1 p.Arg744= (c.2230C>A) is classified Conflicting classifications of pathogenicity in CRB1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-15). Ultra-rare (popmax 0.0495%, mid); Associated with Leber congenital amaurosis 8.

What condition is associated with CRB1 p.Arg744= (c.2230C>A)?

CRB1 p.Arg744= (c.2230C>A) is associated with Leber congenital amaurosis 8, pigmented paravenous retinochoroidal atrophy, retinitis pigmentosa 12 (ClinVar).

How common is CRB1 p.Arg744= (c.2230C>A) in the general population?

CRB1 p.Arg744= (c.2230C>A) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

How is Leber congenital amaurosis inherited?

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

CRB1 p.Arg744=

c.2230C>A · rs150412614 · VCV294676

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Conditions

Leber congenital amaurosis 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.13	GERP -0.054
Overall
CADD	1.964	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0495% Middle Eastern · 3/6,060 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00842%

Overall 0.0275% 444/1,613,820 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.878%	114
Remaining individualsnot grpmax-eligible	0.0736%	1,359
Middle Easterngrpmax	0.0495%	2,020
European (non-Finnish)	0.0105%	9,515
Admixed American	0.01%	9,992
African / African-American	0.004%	24,999
Finnishnot grpmax-eligible	0.00156%	63,970
South Asian	0.0011%	91,056

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: CRB1
Protein: p.Arg744=
Coding: c.2230C>A
MANE Select: NM_201253
dbSNP: rs150412614
Type: single nucleotide variant
Location: chr1:197427555 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.19 · 1 PDB
Residue 744: a UniProt-annotated variant site (in lca8); the laminin g-like 2 domain

Full CRB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Leber congenital amaurosis 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pigmented paravenous retinochoroidal atrophy retinitis pigmentosa 12 retinitis pigmentosa

For Leber congenital amaurosis (Orphanet):

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

Similar variants

CRB1 p.Arg744Ter Pathogenic/Likely pathogenic ★★ same residue
CRB1 p.Arg744Gln Uncertain significance ★★ ⚠ same residue
CRB1 p.Arg744fs Pathogenic ★ same residue
CRB1 c.1172-2A>G Likely pathogenic ★★ same condition
CRB1 c.2128+1G>C Pathogenic/Likely pathogenic ★★ same condition
CRB1 c.2129-1G>A Pathogenic/Likely pathogenic ★★ same condition
CRB1 c.2129-1G>C Pathogenic ★★ same condition
CRB1 c.2129-2A>G 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/crb1-p-arg744 (accessed [today's date]).

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