Is CR2 p.Pro464Ser (c.1390C>T) pathogenic?

CR2 p.Pro464Ser (c.1390C>T) is classified Uncertain significance in CR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-09). AlphaMissense: ambiguous (0.5393); Ultra-rare (popmax 0.0187%, afr); Associated with immunodeficiency, common variable, 7.

What condition is associated with CR2 p.Pro464Ser (c.1390C>T)?

CR2 p.Pro464Ser (c.1390C>T) is associated with immunodeficiency, common variable, 7 (ClinVar).

How common is CR2 p.Pro464Ser (c.1390C>T) in the general population?

CR2 p.Pro464Ser (c.1390C>T) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

What do computational predictors say about CR2 p.Pro464Ser (c.1390C>T)?

AlphaMissense predicts ambiguous (score 0.5393) — an in-silico prediction, not a clinical call.

CR2 p.Pro464Ser

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.1390C>T · rs41313740 · VCV473093

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5393 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Conditions

immunodeficiency, common variable, 7

Computational evidence

Protein change
AlphaMissense	0.5393	ambiguous
REVEL	0.568	indeterminate
SaProt	LLR -9.76	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 31 kb · p 0.0053 · regional, not allelic
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% African / African-American · 14/74,862 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.00768% 124/1,613,658 alleles · ultra-rare exomes 111/1,461,550 · genomes 13/152,108 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,347
Remaining individualsnot grpmax-eligible	0.016%	6,246
European (non-Finnish)	0.00831%	12,039
Admixed American	0.00334%	29,978

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.Pro464Ser
Coding: c.1390C>T
MANE Select: NM_001006658
dbSNP: rs41313740
Type: single nucleotide variant
Location: chr1:207470904 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.18 · 9 PDB
Residue 464: the sushi 7 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 p.Pro464Leu Uncertain significance ★★ same residue
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

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-pro464ser (accessed [today's date]).

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