# NM_001771.4(CD22):c.35T>C (p.Val12Ala)

https://sugi.bio/variant/cd22-p-val12ala

## Summary

**CD22 p.Val12Ala (c.35T>C)** is classified **Uncertain significance** in CD22 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-27). AlphaMissense: likely benign (0.1423); Ultra-rare (popmax 0.0166%, mid).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0166%, mid)

## 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.Val12Ala |
| Coding change (HGVS c.) | c.35T>C |
| MANE Select transcript | [NM_001771](https://www.ncbi.nlm.nih.gov/nuccore/NM_001771) |
| Variant type | single nucleotide variant |
| Location | chr19:35332547-35332547 (GRCh38) |
| ClinVar | [VCV3829457](https://www.ncbi.nlm.nih.gov/clinvar/variation/3829457/) |

**All HGVS expressions:** `NC_000019.10:g.35332547T>C`, `NC_000019.9:g.35823450T>C`, `NM_001185099.2:c.35T>C`, `NM_001185100.2:c.35T>C`, `NM_001185101.2:c.35T>C`, `NM_001278417.2:c.-363-6T>C`, `NM_001771.4:c.35T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1423)
- REVEL 0.065 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.402 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.24) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.894, GERP 0.078, phastCons 0.322 — weakly conserved position
- CADD: **PHRED 13.5**. 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 deltas (raw): acceptor loss **0.24**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.24**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0166%** (mid) · FAF95 7.9e-05% · FAF99 5.4e-05% · 1/6,042 in the highest group · 7/1,610,578 alleles overall — ultra-rare (popmax 0.0166%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0166% | 6,042 |
| African / African-American | 0.00134% | 74,774 |
| South Asian | 0.0011% | 90,672 |
| European (non-Finnish) | 0.000339% | 294,603 |

*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}


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 2025-02-27.

**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 | 2025-02-27 |

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

## Similar variants {#similar}

Related CD22 variant pages (same residue, condition, or type): [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), [CD22 p.Ala656Thr](/variant/cd22-p-ala656thr).

### 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 3829457). 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.*