Is CR2 p.Pro404Ala (c.1210C>G) pathogenic?

CR2 p.Pro404Ala (c.1210C>G) is classified Uncertain significance in CR2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-10-25). AlphaMissense: likely benign (0.1803); Rare (popmax 0.101%, nfe); Associated with systemic lupus erythematosus, susceptibility to, 9.

What condition is associated with CR2 p.Pro404Ala (c.1210C>G)?

CR2 p.Pro404Ala (c.1210C>G) is associated with systemic lupus erythematosus, susceptibility to, 9, immunodeficiency, common variable, 2, immunodeficiency, common variable, 7 (ClinVar).

How common is CR2 p.Pro404Ala (c.1210C>G) in the general population?

CR2 p.Pro404Ala (c.1210C>G) is rare (popmax 0.101%, nfe) (gnomAD).

What do computational predictors say about CR2 p.Pro404Ala (c.1210C>G)?

AlphaMissense predicts likely benign (score 0.1803) — an in-silico prediction, not a clinical call.

CR2 p.Pro404Ala

c.1210C>G · rs148388565 · VCV578201

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1803 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.101%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

systemic lupus erythematosus, susceptibility to, 9

Computational evidence

Protein change
AlphaMissense	0.1803	likely benign
REVEL	0.525	indeterminate
SaProt	LLR -10.48	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 31 kb · p 0.0053 · regional, not allelic
Overall
CADD	23.5	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 0.101% European (non-Finnish) · 1,189/1,179,882 alleles

Filtering AF 0.096% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.094%

Overall 0.0781% 1,261/1,613,586 alleles · rare exomes 1,211/1,461,394 · genomes 50/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.101%	992
Remaining individualsnot grpmax-eligible	0.0561%	1,784
Finnishnot grpmax-eligible	0.0422%	2,371
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,799
African / African-American	0.00668%	14,974
Admixed American	0.005%	19,989

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.Pro404Ala
Coding: c.1210C>G
MANE Select: NM_001006658
dbSNP: rs148388565
Type: single nucleotide variant
Location: chr1:207470087 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.18 · 9 PDB
Residue 404: the sushi 6 domain

Full CR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

systemic lupus erythematosus, susceptibility to, 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: immunodeficiency, common variable, 2 immunodeficiency, common variable, 7

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-pro404ala (accessed [today's date]).

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