Is CRB2 p.Pro1217= (c.3651G>A) pathogenic?

CRB2 p.Pro1217= (c.3651G>A) is classified Likely benign in CRB2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-02-16). Ultra-rare (popmax 0.0207%, mid); Associated with CRB2-related disorder.

What condition is associated with CRB2 p.Pro1217= (c.3651G>A)?

CRB2 p.Pro1217= (c.3651G>A) is associated with CRB2-related disorder (ClinVar).

How common is CRB2 p.Pro1217= (c.3651G>A) in the general population?

CRB2 p.Pro1217= (c.3651G>A) is ultra-rare (popmax 0.0207%, mid) (gnomAD).

CRB2 p.Pro1217=

c.3651G>A · rs201712752 · VCV3031867

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0207%, mid)

Conditions

CRB2-related disorder

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 -7.2	GERP -4.6
Overall
CADD	0.191	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0207% Middle Eastern · 1/4,842 alleles

Filtering AF 0.0148% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0141%

Overall 0.013% 209/1,608,388 alleles · ultra-rare exomes 203/1,456,096 · genomes 6/152,292 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0207%	4,842
European (non-Finnish)	0.0167%	5,984
Admixed American	0.0134%	7,442
Remaining individualsnot grpmax-eligible	0.00482%	20,736

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.Pro1217=
Coding: c.3651G>A
MANE Select: NM_173689
dbSNP: rs201712752
Type: single nucleotide variant
Location: chr9:123376855 (GRCh38)
Gene constraint: LOEUF 1.202 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.95 · 1 PDB
Residue 1217: a UniProt-annotated variant site (in vmckd; uncertain significance); 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

CRB2-related disorder

Similar variants

CRB2 p.Pro1217Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CRB2 p.Arg1128Cys Uncertain significance ★★ same condition
CRB2 p.Asp594Gly Uncertain significance ★★ ⚠ same condition
CRB2 p.Gln851Ter Likely pathogenic ★ same condition
CRB2 p.Trp976Ter Likely pathogenic ★ same condition
CRB2 p.Arg1115Cys Likely pathogenic ⚠ same condition
CRB2 p.Arg903Cys Uncertain significance ⚠ same condition
CRB2 p.Glu356Lys 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-pro1217 (accessed [today's date]).

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