Is CR2 p.Ile776= (c.2328T>C) pathogenic?

CR2 p.Ile776= (c.2328T>C) is classified Benign/Likely benign in CR2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 11.2%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with immunodeficiency, common variable, 7.

What condition is associated with CR2 p.Ile776= (c.2328T>C)?

CR2 p.Ile776= (c.2328T>C) is associated with immunodeficiency, common variable, 7 (ClinVar).

CR2 p.Ile776=

Q: How common is CR2 p.Ile776= (c.2328T>C) in the general population?

CR2 p.Ile776= (c.2328T>C) is common (popmax 11.2%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Common variable immunodeficiency phenotype due to CD21 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.2328T>C · rs61735651 · VCV618588

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 11.2%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

immunodeficiency, common variable, 7

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 0.16	GERP -3.4, phastCons 0.02
Overall
CADD	7.671	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 11.2% European (non-Finnish) · 131,979/1,179,610 alleles

Filtering AF 11.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.1%

Overall 9.9% 159,785/1,613,606 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	11.2%	9
African / African-American	10.9%	9
Remaining individualsnot grpmax-eligible	8.65%	12
Finnishnot grpmax-eligible	6.65%	15
South Asian	5.67%	18
Ashkenazi Jewishnot grpmax-eligible	5.48%	18
Amishnot grpmax-eligible	5.37%	19
Middle Eastern	4.79%	21
Admixed American	4.77%	21
East Asian	0.0334%	2,991

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: CR2
Protein: p.Ile776=
Coding: c.2328T>C
MANE Select: NM_001006658
dbSNP: rs61735651
Type: single nucleotide variant
Location: chr1:207474828 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.18 · 9 PDB
Residue 776: the sushi 12 domain; a disulfide bond

Full CR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency, common variable, 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Common variable immunodeficiency phenotype due to CD21 deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

CR2 c.1225+1G>C Pathogenic ★★ same condition
CR2 c.3089-1G>A Likely pathogenic ★★ same condition
CR2 p.Arg142Ter Pathogenic/Likely pathogenic ★★ same condition
CR2 p.Arg368Ter Pathogenic/Likely pathogenic ★★ same condition
CR2 p.Arg392Ter Pathogenic/Likely pathogenic ★★ same condition
CR2 p.Arg840Ter Pathogenic/Likely pathogenic ★★ same condition
CR2 p.Cys154Ter Pathogenic ★★ same condition
CR2 p.Ala174Pro 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/cr2-p-ile776 (accessed [today's date]).

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