Is CRB1 p.Pro941= (c.2823G>A) pathogenic?

CRB1 p.Pro941= (c.2823G>A) is classified Likely benign in CRB1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-31). Ultra-rare (popmax 0.0121%, sas); Associated with Leber congenital amaurosis 8.

What condition is associated with CRB1 p.Pro941= (c.2823G>A)?

CRB1 p.Pro941= (c.2823G>A) is associated with Leber congenital amaurosis 8, pigmented paravenous retinochoroidal atrophy, retinitis pigmentosa 12 (ClinVar).

How common is CRB1 p.Pro941= (c.2823G>A) in the general population?

CRB1 p.Pro941= (c.2823G>A) is ultra-rare (popmax 0.0121%, sas) (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.Pro941=

c.2823G>A · rs62645757 · VCV99889

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

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 1.4	GERP -0.16, phastCons 0.03
Overall
CADD	6.334	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0121% South Asian · 11/91,076 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00341% 55/1,613,788 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,280
East Asian	0.00446%	22,436
European (non-Finnish)	0.00322%	31,051
Remaining individualsnot grpmax-eligible	0.0032%	31,231
African / African-American	0.00267%	37,433

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.Pro941=
Coding: c.2823G>A
MANE Select: NM_201253
dbSNP: rs62645757
Type: single nucleotide variant
Location: chr1:197429595 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.19 · 1 PDB
Residue 941: a UniProt-annotated variant site (in lca8); the egf-like 14 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 Leber congenital amaurosis

For Leber congenital amaurosis (Orphanet):

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

Similar variants

CRB1 p.Pro941Thr Uncertain significance ★★ ⚠ same residue
CRB1 p.Pro941Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro941 (accessed [today's date]).

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