Is CR2 p.Cys495Tyr (c.1484G>A) pathogenic?

CR2 p.Cys495Tyr (c.1484G>A) is classified Uncertain significance in CR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). AlphaMissense: likely pathogenic (0.8646); Very rare (popmax 8.48e-05%, nfe); Associated with immunodeficiency, common variable, 7.

What condition is associated with CR2 p.Cys495Tyr (c.1484G>A)?

CR2 p.Cys495Tyr (c.1484G>A) is associated with immunodeficiency, common variable, 7 (ClinVar).

How common is CR2 p.Cys495Tyr (c.1484G>A) in the general population?

CR2 p.Cys495Tyr (c.1484G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CR2 p.Cys495Tyr (c.1484G>A)?

AlphaMissense predicts likely pathogenic (score 0.8646) — an in-silico prediction, not a clinical call.

CR2 p.Cys495Tyr

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.1484G>A · rs2527218181 · VCV2201752

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8646 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency, common variable, 7

Computational evidence

Protein change
AlphaMissense	0.8646	likely pathogenic · top 8% in CR2
REVEL	0.744	pathogenic-leaning
SaProt	LLR -11.59	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 31 kb · p 0.0053 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,804 alleles

Overall 6.2e-05% 1/1,613,594 alleles · very rare exomes 1/1,461,280 · genomes 0/152,314 · joint denominator

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.Cys495Tyr
Coding: c.1484G>A
MANE Select: NM_001006658
dbSNP: rs2527218181
Type: single nucleotide variant
Location: chr1:207471078 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.18 · 9 PDB
Residue 495: the sushi 8 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-cys495tyr (accessed [today's date]).

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