Is CR2 p.Arg520Pro (c.1559G>C) pathogenic?

CR2 p.Arg520Pro (c.1559G>C) is classified Uncertain significance in CR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-01). AlphaMissense: ambiguous (0.3606); Very rare (popmax 0.000255%, nfe); Associated with immunodeficiency, common variable, 7.

What condition is associated with CR2 p.Arg520Pro (c.1559G>C)?

CR2 p.Arg520Pro (c.1559G>C) is associated with immunodeficiency, common variable, 7 (ClinVar).

How common is CR2 p.Arg520Pro (c.1559G>C) in the general population?

CR2 p.Arg520Pro (c.1559G>C) is very rare (popmax 0.000255%, nfe) (gnomAD).

What do computational predictors say about CR2 p.Arg520Pro (c.1559G>C)?

AlphaMissense predicts ambiguous (score 0.3606) — an in-silico prediction, not a clinical call.

CR2 p.Arg520Pro

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.1559G>C · rs772909129 · VCV1914779

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3606 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

immunodeficiency, common variable, 7

Computational evidence

Protein change
AlphaMissense	0.3606	ambiguous
REVEL	0.203	benign-leaning
SaProt	LLR -1.06	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.4	GERP 0.72, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 31 kb · p 0.0053 · regional, not allelic
Overall
CADD	21.2	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 0.000255% European (non-Finnish) · 3/1,175,762 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000249% 4/1,609,288 alleles · very rare exomes 4/1,457,044 · genomes 0/152,244 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,334
European (non-Finnish)grpmax	0.000255%	391,920

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg520Pro
Coding: c.1559G>C
MANE Select: NM_001006658
dbSNP: rs772909129
Type: single nucleotide variant
Location: chr1:207471488 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.18 · 9 PDB
Residue 520: the sushi 8 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.Arg520Cys Uncertain significance ★ ⚠ same residue
CR2 p.Arg520His Uncertain significance ★ ⚠ same residue
CR2 p.Arg520Ser 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

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-arg520pro (accessed [today's date]).

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