# NM_001772.4(CD33):c.913T>C (p.Ser305Pro)

https://sugi.bio/variant/cd33-p-ser305pro

## Summary

**CD33 p.Ser305Pro (c.913T>C)** is classified **Benign** in CD33 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-06-10). AlphaMissense: likely benign (0.0487); Common (popmax 30.3%, afr) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Multiple submitters · rsID rs61736475 · 2 submitters · AlphaMissense likely benign · common (popmax 30.3%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

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

*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.Ser305Pro |
| Coding change (HGVS c.) | c.913T>C |
| MANE Select transcript | [NM_001772](https://www.ncbi.nlm.nih.gov/nuccore/NM_001772) |
| dbSNP | [rs61736475](https://www.ncbi.nlm.nih.gov/snp/rs61736475/) |
| Variant type | single nucleotide variant |
| Location | chr19:51235665-51235665 (GRCh38) |
| ClinVar | [VCV1295125](https://www.ncbi.nlm.nih.gov/clinvar/variation/1295125/) |

**All HGVS expressions:** `NC_000019.10:g.51235665T>C`, `NC_000019.9:g.51738920T>C`, `NM_001082618.2:c.532T>C`, `NM_001177608.2:c.913T>C`, `NM_001772.4:c.913T>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 30.3%, afr) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.0487)
- REVEL 0.005 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.202 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -7.018, GERP -2.95 — fast-evolving / accelerated position
- CADD: **PHRED 0.038**. 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 0.91** across the covering region of the MANE Select transcript (51,225,119–51,239,685), spanning 14,566 bp. Chi-square p 0.052. 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 (T>A, Δ0.20 donor 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 **30.3%** (afr) · FAF95 30% · FAF99 29.8% · 22,677/74,830 in the highest group · 56,431/1,613,040 alleles overall — common (popmax 30.3%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 30.3% | 3 |
| Middle Eastern | 4.77% | 21 |
| Remaining individuals (not grpmax-eligible) | 4.17% | 24 |
| Admixed American | 3.28% | 30 |
| European (non-Finnish) | 2.28% | 44 |
| South Asian | 1.66% | 60 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.801% | 125 |
| Finnish (not grpmax-eligible) | 0.458% | 218 |
| Amish (not grpmax-eligible) | 0.329% | 304 |
| East Asian | 0.029% | 3,451 |

*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}

Residue **305** lies in the 'disordered' region.

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. p.Ser305Pro falls in the disordered region. 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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-06-10.

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 2 submissions (2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2021-06-10 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related CD33 variant pages (same residue, condition, or type): [CD33 p.Asp51Asn](/variant/cd33-p-asp51asn), [CD33 c.924+295A>G](/variant/cd33-c-924-plus-295a-g), [CD33 c.924+296C>T](/variant/cd33-c-924-plus-296c-t), [CD33 c.924+2T>C](/variant/cd33-c-924-plus-2t-c), [CD33 c.924+469G>C](/variant/cd33-c-924-plus-469g-c), [CD33 c.*201G>C](/variant/cd33-c-star-201g-c), [CD33 p.Ala14Val](/variant/cd33-p-ala14val), [CD33 p.Ala65Pro](/variant/cd33-p-ala65pro).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 1295125). 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.*