# NM_001145252.3(CFP):c.120C>T (p.Ser40=)

https://sugi.bio/variant/cfp-p-ser40

## Summary

**CFP p.Ser40= (c.120C>T)** is classified **Likely benign** in CFP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-22). Very rare (popmax 0.00309%, eas).

**At a glance:** Likely benign · review: Single submitter · rsID rs763653323 · 1 submitter · very rare (popmax 0.00309%, eas)

## For patients & families {#patients}

This is a change in the CFP 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 | [CFP](https://sugi.bio/atlas/gene/CFP/) |
| Protein change (HGVS p.) | p.Ser40= |
| Coding change (HGVS c.) | c.120C>T |
| MANE Select transcript | [NM_001145252](https://www.ncbi.nlm.nih.gov/nuccore/NM_001145252) |
| dbSNP | [rs763653323](https://www.ncbi.nlm.nih.gov/snp/rs763653323/) |
| Variant type | single nucleotide variant |
| Location | chrX:47629631-47629631 (GRCh38) |
| ClinVar | [VCV1662948](https://www.ncbi.nlm.nih.gov/clinvar/variation/1662948/) |

**All HGVS expressions:** `LRG_129:g.5675C>T`, `LRG_129t1:c.120C>T`, `NC_000023.10:g.47489030G>A`, `NC_000023.11:g.47629631G>A`, `NG_009893.1:g.5675C>T`, `NM_001145252.3:c.120C>T`, `NM_002621.2:c.120C>T`

## 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 -7.649, GERP -3.17 — fast-evolving / accelerated position
- CADD: **PHRED 0.147**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.47 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 **0.00309%** (eas) · 1/32,380 in the highest group · 3/1,061,101 alleles overall — very rare (popmax 0.00309%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00309% | 32,380 |
| Admixed American | 0.00255% | 39,139 |
| European (non-Finnish) | 0.000114% | 875,672 |

*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.*

## Protein context {#protein}

Residue **40** lies in the tsp type-1 0 domain; a disulfide bond; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 83.75, 56% of residues very-high.

**14 experimental structure(s)** (PDB): [1W0R](https://www.rcsb.org/structure/1W0R), [1W0S](https://www.rcsb.org/structure/1W0S), [6RUR](https://www.rcsb.org/structure/6RUR), [6RUS](https://www.rcsb.org/structure/6RUS), [6RUV](https://www.rcsb.org/structure/6RUV), [6RV6](https://www.rcsb.org/structure/6RV6).

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

*Describes the biological roles of CFP (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:** p.Ser40= falls in the tsp type-1 0 domain. In Reactome, CFP is annotated in disease pathway(s) including **Defective B3GALTL causes PpS**.

**Disease mechanism (Reactome):** CFP loss or alteration is curated in [Defective B3GALTL causes PpS](https://reactome.org/content/detail/R-HSA-5083635).

### Pathways affected {#pathways}

CFP participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective B3GALTL causes PpS](https://reactome.org/content/detail/R-HSA-5083635) | curated |
| [Activation of C3 and C5](https://reactome.org/content/detail/R-HSA-174577) | curated |
| [Alternative complement activation](https://reactome.org/content/detail/R-HSA-173736) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [O-glycosylation of TSR domain-containing proteins](https://reactome.org/content/detail/R-HSA-5173214) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |

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

**Biological process:** positive regulation of complement activation, alternative pathway, protein stabilization.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-07-22.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2021-07-22 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CFP variant pages (same residue, condition, or type): [CFP p.Ser40Pro](/variant/cfp-p-ser40pro), [CFP p.Trp321Gly](/variant/cfp-p-trp321gly), [CFP p.Ala402Gly](/variant/cfp-p-ala402gly), [CFP p.Arg157Gln](/variant/cfp-p-arg157gln), [CFP p.Arg157Trp](/variant/cfp-p-arg157trp), [CFP p.Arg159Cys](/variant/cfp-p-arg159cys), [CFP p.Arg247Trp](/variant/cfp-p-arg247trp), [CFP p.Arg438Trp](/variant/cfp-p-arg438trp).

### 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 1662948). 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.*