# NM_001772.4(CD33):c.713_731del (p.Pro238fs)

https://sugi.bio/variant/cd33-p-pro238fs

## Summary

**CD33 p.Pro238fs (c.713_731del)** is classified **Likely benign** in CD33 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2024-09-19). Low-frequency (popmax 2.29%, eas); Associated with CD33-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs201473304 · 2 submitters · 1 linked condition · low-frequency (popmax 2.29%, eas)

## For patients & families {#patients}

This is a change in the CD33 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to CD33-related disorder.

*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 | [CD33](https://sugi.bio/atlas/gene/CD33/) |
| Protein change (HGVS p.) | p.Pro238fs |
| Coding change (HGVS c.) | c.713_731del |
| MANE Select transcript | [NM_001772](https://www.ncbi.nlm.nih.gov/nuccore/NM_001772) |
| dbSNP | [rs201473304](https://www.ncbi.nlm.nih.gov/snp/rs201473304/) |
| Variant type | Deletion |
| Location | chr19:51226322-51226340 (GRCh38) |
| ClinVar | [VCV3056025](https://www.ncbi.nlm.nih.gov/clinvar/variation/3056025/) |

**All HGVS expressions:** `NC_000019.10:g.51226324_51226342del`, `NC_000019.9:g.51729580_51729598del`, `NM_001082618.2:c.332_350del`, `NM_001177608.2:c.713_731del`, `NM_001772.4:c.713_731del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -1.22, GERP -3.26 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.072, pLI 1.2367e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 7**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 21.6**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **2.29%** (eas) · FAF95 2.17% · FAF99 2.13% · 1,023/44,658 in the highest group · 1,100/1,613,710 alleles overall — low-frequency (popmax 2.29%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 2.29% | 44 |
| Remaining individuals (not grpmax-eligible) | 0.0688% | 1,453 |
| South Asian | 0.0176% | 5,691 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00676% | 14,802 |
| Admixed American | 0.00333% | 30,007 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,004 |
| African / African-American | 0.00133% | 75,028 |
| European (non-Finnish) | 0.00102% | 98,324 |

*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}

**CD33** population constraint: LOEUF 1.072, pLI 1.2367e-07, missense-Z 0.97413. *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 78.30, 57% of residues very-high.

**11 experimental structure(s)** (PDB): [5IHB](https://www.rcsb.org/structure/5IHB), [5J06](https://www.rcsb.org/structure/5J06), [5J0B](https://www.rcsb.org/structure/5J0B), [6D48](https://www.rcsb.org/structure/6D48), [6D49](https://www.rcsb.org/structure/6D49), [6D4A](https://www.rcsb.org/structure/6D4A).

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

*Describes the biological roles of CD33 (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:** CD33's established molecular role includes protein tyrosine phosphatase activator activity. In Reactome, CD33 is annotated in disease pathway(s) including **Dengue Virus Attachment and Entry**.

**Disease mechanism (Reactome):** CD33 loss or alteration is curated in [Dengue Virus Attachment and Entry](https://reactome.org/content/detail/R-HSA-9918485).

### Pathways affected {#pathways}

CD33 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus Attachment and Entry](https://reactome.org/content/detail/R-HSA-9918485) | curated |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |

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

**Molecular function:** protein tyrosine phosphatase activator activity, protein phosphatase binding, sialic acid binding.

**Biological process:** immune response-inhibiting signal transduction, negative regulation of interleukin-1 beta production, negative regulation of interleukin-8 production, negative regulation of tumor necrosis factor production, Fc-gamma receptor signaling pathway, positive regulation of protein secretion.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-09-19.

**Submitter consensus:** unanimous (1/1 Likely benign).

**Submission history:** 15 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-09-19 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |

## Associated conditions {#conditions}

[CD33-related disorder](https://sugi.bio/atlas/disease/cd33-related-disorder/).

**Reported phenotype names (ClinVar):** CD33-related disorder, Clear cell carcinoma of kidney, Familial cancer of breast, Gastric cancer, Papillary renal cell carcinoma type 1, Melanoma, Hepatocellular carcinoma, Malignant tumor of esophagus, Malignant lymphoma, large B-cell, diffuse, CD33-related condition.

## Similar variants {#similar}

Related CD33 variant pages (same residue, condition, or type): [CD33 p.Ile47_Pro48insAsnIle](/variant/cd33-p-ile47-pro48insasnile), [CD33 p.Gly156fs](/variant/cd33-p-gly156fs).

### 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 3056025). 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.*