# NM_000574.5(CD55):c.334C>T (p.Pro112Ser)

https://sugi.bio/variant/cd55-p-pro112ser

## Summary

**CD55 p.Pro112Ser (c.334C>T)** is classified **Uncertain significance** in CD55 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-20). AlphaMissense: likely benign (0.1824); Very rare (popmax 0.00838%, amr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00838%, amr)

## For patients & families {#patients}

This is a change in the CD55 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [CD55](https://sugi.bio/atlas/gene/CD55/) |
| Protein change (HGVS p.) | p.Pro112Ser |
| Coding change (HGVS c.) | c.334C>T |
| MANE Select transcript | [NM_000574](https://www.ncbi.nlm.nih.gov/nuccore/NM_000574) |
| Variant type | single nucleotide variant |
| Location | chr1:207324606-207324606 (GRCh38) |
| ClinVar | [VCV3998281](https://www.ncbi.nlm.nih.gov/clinvar/variation/3998281/) |

**All HGVS expressions:** `LRG_127:g.8135C>T`, `LRG_127t1:c.334C>T`, `NC_000001.10:g.207497951C>T`, `NC_000001.11:g.207324606C>T`, `NG_007465.1:g.8135C>T`, `NM_000574.5:c.334C>T`, `NM_001114752.3:c.334C>T`, `NM_001300902.2:c.334C>T`, `NM_001300903.2:c.334C>T`, `NM_001300904.2:c.334C>T`, `NR_125349.2:n.422C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1824)
- REVEL 0.064 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.23 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -3.678, GERP -4.34 — fast-evolving / accelerated position
- CADD: **PHRED 0.003**. 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 0.68** across the covering region of the MANE Select transcript (207,322,528–207,326,826), spanning 4,298 bp. Chi-square p 4.2e-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>G, Δ0.52 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 **0.00838%** (amr) · FAF95 0.00325% · FAF99 0.00208% · 5/59,680 in the highest group · 7/1,611,480 alleles overall — very rare (popmax 0.00838%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00838% | 11,936 |
| East Asian | 0.00223% | 44,794 |
| European (non-Finnish) | 8.48e-05% | 1,178,766 |

*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}

**CD55** population constraint: LOEUF 1.234, pLI 1.1051e-06, missense-Z 0.32192. *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 **112** lies in the sushi 2 domain.

AlphaFold model confidence (whole protein): pLDDT 78.99, 66% of residues very-high.

**33 experimental structure(s)** (PDB): [1H03](https://www.rcsb.org/structure/1H03), [1H04](https://www.rcsb.org/structure/1H04), [1H2P](https://www.rcsb.org/structure/1H2P), [1H2Q](https://www.rcsb.org/structure/1H2Q), [1M11](https://www.rcsb.org/structure/1M11), [1NWV](https://www.rcsb.org/structure/1NWV).

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

*Describes the biological roles of CD55 (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:** CD55's established molecular role includes virus receptor activity. p.Pro112Ser falls in the sushi 2 domain.


### Pathways affected {#pathways}

CD55 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [COPI-mediated anterograde transport](https://reactome.org/content/detail/R-HSA-6807878) | curated |
| [Class B/2 (Secretin family receptors)](https://reactome.org/content/detail/R-HSA-373080) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |

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

**Molecular function:** virus receptor activity, lipid binding.

**Biological process:** positive regulation of T cell cytokine production, positive regulation of cytosolic calcium ion concentration, regulation of complement activation, regulation of lipopolysaccharide-mediated signaling pathway, negative regulation of complement activation, regulation of complement-dependent cytotoxicity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-20.

**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 | 2025-03-20 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related CD55 variant pages (same residue, condition, or type): [CD55 p.Arg221Ser](/variant/cd55-p-arg221ser), [CD55 p.Asn171Ser](/variant/cd55-p-asn171ser), [CD55 p.Asn44Asp](/variant/cd55-p-asn44asp), [CD55 p.Glu273Gly](/variant/cd55-p-glu273gly), [CD55 p.His339Asn](/variant/cd55-p-his339asn), [CD55 p.Leu374Val](/variant/cd55-p-leu374val), [CD55 p.Met377Thr](/variant/cd55-p-met377thr), [CD55 p.Met377Val](/variant/cd55-p-met377val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3998281). 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.*