# NM_001771.4(CD22):c.606C>A (p.Ser202Arg)

https://sugi.bio/variant/cd22-p-ser202arg

## Summary

**CD22 p.Ser202Arg (c.606C>A)** is classified **Uncertain significance** in CD22 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely pathogenic (0.8448); Ultra-rare (popmax 0.0263%, sas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs764611503 · 1 submitter · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0263%, sas)

## For patients & families {#patients}

This is a change in the CD22 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CD22](https://sugi.bio/atlas/gene/CD22/) |
| Protein change (HGVS p.) | p.Ser202Arg |
| Coding change (HGVS c.) | c.606C>A |
| MANE Select transcript | [NM_001771](https://www.ncbi.nlm.nih.gov/nuccore/NM_001771) |
| dbSNP | [rs764611503](https://www.ncbi.nlm.nih.gov/snp/rs764611503/) |
| Variant type | single nucleotide variant |
| Location | chr19:35336229-35336229 (GRCh38) |
| ClinVar | [VCV3140450](https://www.ncbi.nlm.nih.gov/clinvar/variation/3140450/) |

**All HGVS expressions:** `NC_000019.10:g.35336229C>A`, `NC_000019.9:g.35827132C>A`, `NM_001185099.2:c.606C>A`, `NM_001185100.2:c.606C>A`, `NM_001185101.2:c.606C>A`, `NM_001278417.2:c.90C>A`, `NM_001771.4:c.606C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8448)
- REVEL 0.639 (indeterminate)
- SaProt LLR -11.879 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP -0.02, GERP -4.1, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- AlphaMissense ranks this among the **top 6%** most-pathogenic-predicted substitutions in CD22 (of 4,985 modeled).
- CADD: **PHRED 19.38**. 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.*
- Regional missense constraint: **o/e 0.88** across the covering region of the MANE Select transcript (35,332,041–35,346,694), spanning 14,653 bp. Chi-square p 7.1e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.43 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0263%** (sas) · FAF95 0.0181% · FAF99 0.0154% · 24/91,090 in the highest group · 28/1,614,222 alleles overall — ultra-rare (popmax 0.0263%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0263% | 3,795 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,837 |
| East Asian | 0.00223% | 44,878 |

*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}

**CD22** population constraint: LOEUF 0.639, pLI 4.8504e-06, missense-Z 1.9774. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **202** lies in the ig-like c2-type 1 domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 79.33, 51% of residues very-high.

**7 experimental structure(s)** (PDB): [5VKJ](https://www.rcsb.org/structure/5VKJ), [5VKM](https://www.rcsb.org/structure/5VKM), [5VL3](https://www.rcsb.org/structure/5VL3), [7O52](https://www.rcsb.org/structure/7O52), [9RO7](https://www.rcsb.org/structure/9RO7), [9ROB](https://www.rcsb.org/structure/9ROB).

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

*Describes the biological roles of CD22 (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.*


### Pathways affected {#pathways}

CD22 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CD22 mediated BCR regulation](https://reactome.org/content/detail/R-HSA-5690714) | curated |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | curated |
| [Antigen activates B Cell Receptor (BCR) leading to generation of second messengers](https://reactome.org/content/detail/R-HSA-983695) | electronic |

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

**Biological process:** regulation of endocytosis, B cell activation, negative regulation of B cell receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-07.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-07 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CD22 variant pages (same residue, condition, or type): [CD22 p.Ser202Asn](/variant/cd22-p-ser202asn), [CD22 p.Ala391Thr](/variant/cd22-p-ala391thr), [CD22 p.Cys265=](/variant/cd22-p-cys265), [CD22 p.Gly551Arg](/variant/cd22-p-gly551arg), [CD22 p.Gly727Ser](/variant/cd22-p-gly727ser), [CD22 p.Pro681=](/variant/cd22-p-pro681), [CD22 p.Ala17Val](/variant/cd22-p-ala17val), [CD22 p.Ala498Ser](/variant/cd22-p-ala498ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 3140450). 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.*