Is CRB1 p.Cys670= (c.2010T>C) pathogenic?

CRB1 p.Cys670= (c.2010T>C) is classified Conflicting classifications of pathogenicity in CRB1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-20). Ultra-rare (popmax 0.0713%, eas); Associated with Leber congenital amaurosis 8.

What condition is associated with CRB1 p.Cys670= (c.2010T>C)?

CRB1 p.Cys670= (c.2010T>C) is associated with Leber congenital amaurosis 8, pigmented paravenous retinochoroidal atrophy, retinitis pigmentosa 12 (ClinVar).

How common is CRB1 p.Cys670= (c.2010T>C) in the general population?

CRB1 p.Cys670= (c.2010T>C) is ultra-rare (popmax 0.0713%, eas) (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.Cys670=

c.2010T>C · rs201949837 · VCV294673

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0713%, eas)

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 -0.95	GERP -3.8
Overall
CADD	4.001	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0713% East Asian · 32/44,876 alleles

Filtering AF 0.0519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0452%

Overall 0.00204% 33/1,614,196 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0713%	1,402
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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.Cys670=
Coding: c.2010T>C
MANE Select: NM_201253
dbSNP: rs201949837
Type: single nucleotide variant
Location: chr1:197421838 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.19 · 1 PDB
Residue 670: a UniProt-annotated variant site (in lca8); the laminin g-like 1 domain; a disulfide bond

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.Cys670Ter Likely pathogenic ★ same residue
CRB1 p.Cys670Ser Uncertain significance ★ 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
CRB1 c.2676+1G>A 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/crb1-p-cys670 (accessed [today's date]).

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