# NM_001772.4(CD33):c.155A>G (p.Lys52Arg)

https://sugi.bio/variant/cd33-p-lys52arg

## Summary

**CD33 p.Lys52Arg (c.155A>G)** is classified **Likely benign** in CD33 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-23). AlphaMissense: likely benign (0.062); Ultra-rare (popmax 0.0307%, afr).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0307%, afr)

## For patients & families {#patients}

This is a change in the CD33 gene that is classified as likely benign — not considered disease-causing, 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 | [CD33](https://sugi.bio/atlas/gene/CD33/) |
| Protein change (HGVS p.) | p.Lys52Arg |
| Coding change (HGVS c.) | c.155A>G |
| MANE Select transcript | [NM_001772](https://www.ncbi.nlm.nih.gov/nuccore/NM_001772) |
| Variant type | single nucleotide variant |
| Location | chr19:51225335-51225335 (GRCh38) |
| ClinVar | [VCV3829538](https://www.ncbi.nlm.nih.gov/clinvar/variation/3829538/) |

**All HGVS expressions:** `NC_000019.10:g.51225335A>G`, `NC_000019.9:g.51728591A>G`, `NM_001082618.2:c.37+180A>G`, `NM_001177608.2:c.155A>G`, `NM_001772.4:c.155A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.062)
- REVEL 0.005 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.649 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.23) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -4.139, GERP -3.17 — fast-evolving / accelerated position
- CADD: **PHRED 0.221**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0307%** (afr) · FAF95 0.0209% · FAF99 0.0177% · 23/75,040 in the highest group · 27/1,614,186 alleles overall — ultra-rare (popmax 0.0307%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0307% | 3,263 |
| Admixed American | 0.005% | 20,010 |
| South Asian | 0.0011% | 91,082 |

*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 **52** lies in a disulfide bond; the ig-like v-type domain.

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.Lys52Arg falls in the ig-like v-type domain. 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-23.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-12-23 |

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

## 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 3829538). 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.*