Is CR2 p.Ser663Pro (c.1987T>C) pathogenic?

CR2 p.Ser663Pro (c.1987T>C) is classified Benign/Likely benign in CR2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 49.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with immunodeficiency, common variable, 7.

What condition is associated with CR2 p.Ser663Pro (c.1987T>C)?

CR2 p.Ser663Pro (c.1987T>C) is associated with immunodeficiency, common variable, 7 (ClinVar).

CR2 p.Ser663Pro

Q: How common is CR2 p.Ser663Pro (c.1987T>C) in the general population?

CR2 p.Ser663Pro (c.1987T>C) is common (popmax 49.4%, afr) — 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.1987T>C · rs4308977 · VCV402560

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 49.4%, afr) — 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.
REVEL	0.076	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.74	GERP -3.4, phastCons 0.001
Regional constraint	o/e 0.92	unconstrained · MANE · 31 kb · p 0.0053 · regional, not allelic
Overall
CADD	14.14	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 49.4% African / African-American · 36,964/74,846 alleles

Filtering AF 49% ClinGen BA1/BS1 input FAF95, joint · FAF99 48.8%

Overall 30.8% 495,669/1,609,678 alleles · common exomes 444,806/1,457,606 · genomes 50,863/152,072 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	49.4%	2
Middle Eastern	32.2%	3
European (non-Finnish)	32%	3
Remaining individualsnot grpmax-eligible	29.9%	3
Ashkenazi Jewishnot grpmax-eligible	28.6%	4
South Asian	23.4%	4
Finnishnot grpmax-eligible	22.8%	4
Amishnot grpmax-eligible	20.6%	5
Admixed American	19.4%	5
East Asian	12%	8

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.Ser663Pro
Coding: c.1987T>C
MANE Select: NM_001006658
dbSNP: rs4308977
Type: single nucleotide variant
Location: chr1:207473553 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.18 · 9 PDB
Residue 663: the sushi 11 domain

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-ser663pro (accessed [today's date]).

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