# NM_001006658.3(CR2):c.1383C>G (p.Pro461=)

https://sugi.bio/variant/cr2-p-pro461

## Summary

**CR2 p.Pro461= (c.1383C>G)** is classified **Likely benign** in CR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-03). Ultra-rare (popmax 0.044%, afr); Associated with immunodeficiency, common variable, 7.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs150464766 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.044%, afr)

## For patients & families {#patients}

This is a change in the CR2 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to immunodeficiency, common variable, 7.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Diagnostic panels | CR2 is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015836/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CR2](https://sugi.bio/atlas/gene/CR2/) |
| Protein change (HGVS p.) | p.Pro461= |
| Coding change (HGVS c.) | c.1383C>G |
| MANE Select transcript | [NM_001006658](https://www.ncbi.nlm.nih.gov/nuccore/NM_001006658) |
| dbSNP | [rs150464766](https://www.ncbi.nlm.nih.gov/snp/rs150464766/) |
| Variant type | single nucleotide variant |
| Location | chr1:207470897-207470897 (GRCh38) |
| ClinVar | [VCV1633184](https://www.ncbi.nlm.nih.gov/clinvar/variation/1633184/) |

**All HGVS expressions:** `LRG_348:g.21598C>G`, `LRG_348t1:c.1383C>G`, `NC_000001.10:g.207644242C>G`, `NC_000001.11:g.207470897C>G`, `NG_013006.1:g.21598C>G`, `NM_001006658.2:c.1383C>G`, `NM_001006658.3:c.1383C>G`, `NM_001877.5:c.1383C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.29) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -1.698, GERP -1.25 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.932**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.29**. Largest is donor gain, 19 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.044%** (afr) · FAF95 0.0321% · FAF99 0.0281% · 33/74,984 in the highest group · 40/1,613,778 alleles overall — ultra-rare (popmax 0.044%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.044% | 2,272 |
| East Asian | 0.0134% | 7,479 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,486 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CR2** population constraint: LOEUF 0.871, pLI 1.8413e-20, missense-Z 1.5057. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **immunodeficiency, common variable, 7** — Definitive (AR)

## Protein context {#protein}

Residue **461** lies in the sushi 7 domain.

AlphaFold model confidence (whole protein): pLDDT 75.18, 2% of residues very-high.

**9 experimental structure(s)** (PDB): [1GHQ](https://www.rcsb.org/structure/1GHQ), [1LY2](https://www.rcsb.org/structure/1LY2), [1W2R](https://www.rcsb.org/structure/1W2R), [1W2S](https://www.rcsb.org/structure/1W2S), [2ATY](https://www.rcsb.org/structure/2ATY), [2GSX](https://www.rcsb.org/structure/2GSX).

## What this gene does {#gene-function}

*Describes the biological roles of CR2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CR2's established molecular role includes complement binding. p.Pro461= falls in the sushi 7 domain.


### Pathways affected {#pathways}

CR2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |
| [Affinity selection of immunoglobulins](https://reactome.org/content/detail/R-HSA-9938027) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** complement binding, DNA binding, transmembrane signaling receptor activity, immunoglobulin receptor binding, protein homodimerization activity.

**Biological process:** complement activation, alternative pathway, B cell differentiation, B cell proliferation, B cell activation, symbiont entry into host cell, type I interferon-mediated signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-03.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2019–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-06-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-03 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-09-07 |

## Associated conditions {#conditions}

[immunodeficiency, common variable, 7](https://sugi.bio/atlas/disease/immunodeficiency-common-variable-7/).

**Reported phenotype names (ClinVar):** Immunodeficiency, common variable, 7, CR2-related disorder, not specified, CR2-related condition, CR2-related disorders, AllHighlyPenetrant.

## Similar variants {#similar}

Related CR2 variant pages (same residue, condition, or type): [CR2 p.Pro461Ser](/variant/cr2-p-pro461ser), [CR2 c.1225+1G>C](/variant/cr2-c-1225-plus-1g-c), [CR2 c.3089-1G>A](/variant/cr2-c-3089-minus-1g-a), [CR2 p.Arg142Ter](/variant/cr2-p-arg142ter), [CR2 p.Arg368Ter](/variant/cr2-p-arg368ter), [CR2 p.Arg392Ter](/variant/cr2-p-arg392ter), [CR2 p.Arg840Ter](/variant/cr2-p-arg840ter), [CR2 p.Cys154Ter](/variant/cr2-p-cys154ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1633184). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*