Is CRB1 p.Pro329= (c.987T>C) pathogenic?

CRB1 p.Pro329= (c.987T>C) is classified Uncertain significance in CRB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-12). Very rare (popmax 0.00659%, sas); Associated with Leber congenital amaurosis 8.

What condition is associated with CRB1 p.Pro329= (c.987T>C)?

CRB1 p.Pro329= (c.987T>C) is associated with Leber congenital amaurosis 8, retinitis pigmentosa 12 (ClinVar).

How common is CRB1 p.Pro329= (c.987T>C) in the general population?

CRB1 p.Pro329= (c.987T>C) is very rare (popmax 0.00659%, 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.Pro329=

c.987T>C · rs754038973 · VCV1402861

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00659%, 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 1.1	GERP 0.26, phastCons 1
Overall
CADD	12.89	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/91,082 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000547% 8/1,461,712 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,180
Remaining individualsnot grpmax-eligible	0.0016%	62,502
European (non-Finnish)	8.48e-05%	1,179,908

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.Pro329=
Coding: c.987T>C
MANE Select: NM_201253
dbSNP: rs754038973
Type: single nucleotide variant
Location: chr1:197347478 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.19 · 1 PDB
Residue 329: the egf-like 8 domain; a UniProt-annotated variant site (in lca8); 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: retinitis pigmentosa 12

For Leber congenital amaurosis (Orphanet):

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

Similar variants

CRB1 p.Pro329fs Pathogenic ★ same residue
CRB1 p.Pro329Ser 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-pro329 (accessed [today's date]).

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