# NM_013291.3(CPSF1):c.2115C>T (p.Ser705=)

https://sugi.bio/variant/cpsf1-p-ser705

## Summary

**CPSF1 p.Ser705= (c.2115C>T)** is classified **Likely benign** in CPSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-01). Ultra-rare (popmax 0.0602%, eas).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · ultra-rare (popmax 0.0602%, eas)

## For patients & families {#patients}

This is a change in the CPSF1 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 | [CPSF1](https://sugi.bio/atlas/gene/CPSF1/) |
| Protein change (HGVS p.) | p.Ser705= |
| Coding change (HGVS c.) | c.2115C>T |
| MANE Select transcript | [NM_013291](https://www.ncbi.nlm.nih.gov/nuccore/NM_013291) |
| Variant type | single nucleotide variant |
| Location | chr8:144397838-144397838 (GRCh38) |
| ClinVar | [VCV4820840](https://www.ncbi.nlm.nih.gov/clinvar/variation/4820840/) |

**All HGVS expressions:** `NC_000008.10:g.145623053G>A`, `NC_000008.11:g.144397838G>A`, `NM_013291.3:c.2115C>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 -5.654, GERP -4.07 — fast-evolving / accelerated position
- CADD: **PHRED 6.774**. 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>C, Δ0.28 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 **0.0602%** (eas) · FAF95 0.0424% · FAF99 0.0365% · 27/44,864 in the highest group · 66/1,611,236 alleles overall — ultra-rare (popmax 0.0602%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0602% | 1,662 |
| South Asian | 0.0154% | 6,505 |
| African / African-American | 0.00533% | 18,751 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,211 |
| European (non-Finnish) | 0.00161% | 62,072 |

*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}

**CPSF1** population constraint: LOEUF 0.74, pLI 7.9584e-21, missense-Z 2.0401. *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 **705** lies in a UniProt-annotated variant site (in myp27).

AlphaFold model confidence (whole protein): pLDDT 82.97, 62% of residues very-high.

**13 experimental structure(s)** (PDB): [6BLY](https://www.rcsb.org/structure/6BLY), [6BM0](https://www.rcsb.org/structure/6BM0), [6DNH](https://www.rcsb.org/structure/6DNH), [6F9N](https://www.rcsb.org/structure/6F9N), [6FUW](https://www.rcsb.org/structure/6FUW), [6URG](https://www.rcsb.org/structure/6URG).

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

*Describes the biological roles of CPSF1 (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:** CPSF1's established molecular role includes enzyme binding. In Reactome, CPSF1 is annotated in disease pathway(s) including **Dengue Virus-Host Interactions**.

**Disease mechanism (Reactome):** CPSF1 loss or alteration is curated in [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481).

### Pathways affected {#pathways}

CPSF1 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481) | curated |
| [Processing of Intronless Pre-mRNAs](https://reactome.org/content/detail/R-HSA-77595) | curated |
| [RNA Polymerase II Transcription Termination](https://reactome.org/content/detail/R-HSA-73856) | curated |
| [Transport of Mature mRNA Derived from an Intronless Transcript](https://reactome.org/content/detail/R-HSA-159231) | curated |
| [mRNA 3'-end processing](https://reactome.org/content/detail/R-HSA-72187) | curated |
| [mRNA Polyadenylation](https://reactome.org/content/detail/R-HSA-9770562) | curated |
| [tRNA processing in the nucleus](https://reactome.org/content/detail/R-HSA-6784531) | curated |

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

**Molecular function:** enzyme binding, mRNA 3'-UTR AU-rich region binding.

**Biological process:** mRNA 3'-end processing.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-01 |

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

## Similar variants {#similar}

Related CPSF1 variant pages (same residue, condition, or type): [CPSF1 p.Ala1319Thr](/variant/cpsf1-p-ala1319thr), [CPSF1 p.Thr561Ile](/variant/cpsf1-p-thr561ile), [CPSF1 p.Gly722=](/variant/cpsf1-p-gly722), [CPSF1 p.Leu1360=](/variant/cpsf1-p-leu1360), [CPSF1 p.Pro438=](/variant/cpsf1-p-pro438), [CPSF1 p.Pro654=](/variant/cpsf1-p-pro654), [CPSF1 c.539+1G>A](/variant/cpsf1-c-539-plus-1g-a), [CPSF1 c.1119+2T>G](/variant/cpsf1-c-1119-plus-2t-g).

### 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 4820840). 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.*