Is CR2 p.Arg520Ser (c.1558C>A) pathogenic?

CR2 p.Arg520Ser (c.1558C>A) is classified Uncertain significance in CR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-09). AlphaMissense: ambiguous (0.4213); Very rare (popmax 0.000935%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CR2 p.Arg520Ser (c.1558C>A)?

CR2 p.Arg520Ser (c.1558C>A) is associated with Inborn genetic diseases (ClinVar).

How common is CR2 p.Arg520Ser (c.1558C>A) in the general population?

CR2 p.Arg520Ser (c.1558C>A) is very rare (popmax 0.000935%, nfe) (gnomAD).

What do computational predictors say about CR2 p.Arg520Ser (c.1558C>A)?

AlphaMissense predicts ambiguous (score 0.4213) — an in-silico prediction, not a clinical call.

CR2 p.Arg520Ser

c.1558C>A · rs764276175 · VCV2235490

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4213 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000935%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4213	ambiguous
REVEL	0.15	moderately benign-leaning
SaProt	LLR -3.96	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.31	donor loss · deltas
Pangolin	Δ0.55	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 31 kb · p 0.0053 · regional, not allelic
Overall
CADD	25.0	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 0.000935% European (non-Finnish) · 11/1,176,106 alleles

Filtering AF 0.000502% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000367%

Overall 0.000683% 11/1,609,562 alleles · very rare exomes 11/1,457,442 · genomes 0/152,120 · 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.Arg520Ser
Coding: c.1558C>A
MANE Select: NM_001006658
dbSNP: rs764276175
Type: single nucleotide variant
Location: chr1:207471487 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CR2 p.Arg520Pro Uncertain significance ★★ ⚠ same residue
CR2 p.Arg520Cys Uncertain significance ★ ⚠ same residue
CR2 p.Arg520His Uncertain significance ★ ⚠ same residue
CR2 p.Ala174Pro Uncertain significance ★★ ⚠ same condition
CR2 p.Ala3Ser Uncertain significance ★★ ⚠ same condition
CR2 p.Arg1063Cys Uncertain significance ★★ ⚠ same condition
CR2 p.Arg358Lys Uncertain significance ★★ ⚠ same condition
CR2 p.Arg643Cys 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-arg520ser (accessed [today's date]).

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