# NM_001145252.3(CFP):c.865C>T (p.Pro289Ser)

https://sugi.bio/variant/cfp-p-pro289ser

## Summary

**CFP p.Pro289Ser (c.865C>T)** is classified **Likely benign** in CFP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-21). AlphaMissense: likely benign (0.3287); Ultra-rare (popmax 0.062%, sas).

**At a glance:** Likely benign · review: Single submitter · rsID rs766160459 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.062%, sas)

## 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.Pro289Ser |
| Coding change (HGVS c.) | c.865C>T |
| MANE Select transcript | [NM_001145252](https://www.ncbi.nlm.nih.gov/nuccore/NM_001145252) |
| dbSNP | [rs766160459](https://www.ncbi.nlm.nih.gov/snp/rs766160459/) |
| Variant type | single nucleotide variant |
| Location | chrX:47626848-47626848 (GRCh38) |
| ClinVar | [VCV2168803](https://www.ncbi.nlm.nih.gov/clinvar/variation/2168803/) |

**All HGVS expressions:** `LRG_129:g.8458C>T`, `LRG_129t1:c.865C>T`, `NC_000023.10:g.47486247G>A`, `NC_000023.11:g.47626848G>A`, `NG_009893.1:g.8458C>T`, `NM_001145252.3:c.865C>T`, `NM_002621.2:c.865C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3287)
- REVEL 0.334 (indeterminate)
- SaProt LLR -11.025 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- Conservation: phyloP 11.639, GERP 1.74, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.9**. 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 0.79** across the covering region of the MANE Select transcript (47,624,278–47,629,844), spanning 5,566 bp. Chi-square p 3.9e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for CFP (471 scored positions, the nearest 40 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.062%** (sas) · FAF95 0.0457% · FAF99 0.0402% · 35/56,472 in the highest group · 37/1,209,405 alleles overall — ultra-rare (popmax 0.062%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.062% | 1,613 |
| Remaining individuals (not grpmax-eligible) | 0.00421% | 23,766 |

*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.*

## Protein context {#protein}

Residue **289** lies in the tsp type-1 4 domain.

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.Pro289Ser falls in the tsp type-1 4 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 2024-07-21.

**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 | 2024-07-21 |

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

## Similar variants {#similar}

Related CFP variant pages (same residue, condition, or type): [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), [CFP p.Asn307Ser](/variant/cfp-p-asn307ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2168803). 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.*