Is CRB2 p.Asp322= (c.966C>T) pathogenic?

CRB2 p.Asp322= (c.966C>T) is classified Conflicting classifications of pathogenicity in CRB2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-30). Ultra-rare (popmax 0.018%, mid); Associated with focal segmental glomerulosclerosis 9.

What condition is associated with CRB2 p.Asp322= (c.966C>T)?

CRB2 p.Asp322= (c.966C>T) is associated with focal segmental glomerulosclerosis 9, ventriculomegaly-cystic kidney disease (ClinVar).

How common is CRB2 p.Asp322= (c.966C>T) in the general population?

CRB2 p.Asp322= (c.966C>T) is ultra-rare (popmax 0.018%, mid) (gnomAD).

CRB2 p.Asp322=

c.966C>T · rs753016438 · VCV1576581

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 0.018%, mid)

Conditions

focal segmental glomerulosclerosis 9

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -4.8	GERP -3.8
Overall
CADD	8.161	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.018% Middle Eastern · 1/5,564 alleles

Filtering AF 0.00627% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00429%

Overall 0.00429% 67/1,562,206 alleles · ultra-rare exomes 61/1,410,076 · genomes 6/152,130 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.018%	5,564
East Asian	0.0144%	6,927
African / African-American	0.00544%	18,370
European (non-Finnish)	0.00451%	22,197
Remaining individualsnot grpmax-eligible	0.00331%	30,252
Finnishnot grpmax-eligible	0.00169%	59,162
South Asian	0.00118%	84,698

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: CRB2
Protein: p.Asp322=
Coding: c.966C>T
MANE Select: NM_173689
dbSNP: rs753016438
Type: single nucleotide variant
Location: chr9:123367598 (GRCh38)
Gene constraint: LOEUF 1.202 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.95 · 1 PDB
Residue 322: the 'required for maximum inhibition of app amyloid-beta peptide secretion' region; the egf-like 7; calcium-binding domain; a UniProt-annotated variant site (in fsgs9; uncertain significance)

Full CRB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

focal segmental glomerulosclerosis 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ventriculomegaly-cystic kidney disease

Similar variants

CRB2 p.Asp322Glu Uncertain significance ★ ⚠ same residue
CRB2 p.Arg275Ter Pathogenic ★★ same condition
CRB2 p.Cys105Ter Pathogenic/Likely pathogenic ★★ same condition
CRB2 p.Gly1205Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
CRB2 p.Trp759Ter Pathogenic ★★ same condition
CRB2 p.Ala914Val Uncertain significance ★★ ⚠ same condition
CRB2 p.Arg115Trp Uncertain significance ★★ ⚠ same condition
CRB2 p.Arg466Cys Uncertain significance ★★ ⚠ 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/crb2-p-asp322 (accessed [today's date]).

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