# NM_017437.3(CPSF2):c.800C>T (p.Ala267Val)

https://sugi.bio/variant/cpsf2-p-ala267val

## Summary

**CPSF2 p.Ala267Val (c.800C>T)** is classified **Uncertain significance** in CPSF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-21). AlphaMissense: ambiguous (0.4257); No allele count reported in gnomAD v4.1 (AN 1,613,858).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2545220390 · 1 submitter · AlphaMissense ambiguous · no allele count reported in gnomAD v4.1 (AN 1,613,858)

## For patients & families {#patients}

This is a change in the CPSF2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [CPSF2](https://sugi.bio/atlas/gene/CPSF2/) |
| Protein change (HGVS p.) | p.Ala267Val |
| Coding change (HGVS c.) | c.800C>T |
| MANE Select transcript | [NM_017437](https://www.ncbi.nlm.nih.gov/nuccore/NM_017437) |
| dbSNP | [rs2545220390](https://www.ncbi.nlm.nih.gov/snp/rs2545220390/) |
| Variant type | single nucleotide variant |
| Location | chr14:92142302-92142302 (GRCh38) |
| ClinVar | [VCV3076887](https://www.ncbi.nlm.nih.gov/clinvar/variation/3076887/) |

**All HGVS expressions:** `NC_000014.8:g.92608646C>T`, `NC_000014.9:g.92142302C>T`, `NM_001322270.2:c.800C>T`, `NM_001322271.2:c.341C>T`, `NM_001322272.2:c.800C>T`, `NM_017437.3:c.800C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.4257) — no call either way
- REVEL 0.228 (benign-leaning)
- SaProt LLR -8.569 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense makes no call
- Conservation: phyloP 7.715, GERP 2.31, phastCons 1 — highly conserved
- CADD: **PHRED 22.4**. 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 0.56** across the covering region of the MANE Select transcript (92,130,985–92,143,110), spanning 12,125 bp. Chi-square p 1.9e-17. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,613,858)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**CPSF2** population constraint: LOEUF 0.651, pLI 0.002631, missense-Z 3.4283. *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 **267** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 81.14, 55% of residues very-high.

**6 experimental structure(s)** (PDB): [6URG](https://www.rcsb.org/structure/6URG), [6V4X](https://www.rcsb.org/structure/6V4X), [9NB1](https://www.rcsb.org/structure/9NB1), [9NGO](https://www.rcsb.org/structure/9NGO), [9NH5](https://www.rcsb.org/structure/9NH5), [9NH6](https://www.rcsb.org/structure/9NH6) — incl. mutant structure 9NB1.

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

*Describes the biological roles of CPSF2 (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:** CPSF2 participates in disease-associated pathways. In Reactome, CPSF2 is annotated in disease pathway(s) including **Dengue Virus-Host Interactions**.

**Disease mechanism (Reactome):** CPSF2 loss or alteration is curated in [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481).

### Pathways affected {#pathways}

CPSF2 participates in **6 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 |

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

**Biological process:** mRNA 3'-end processing by stem-loop binding and cleavage, mRNA 3'-end processing.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-21.

**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 | 2023-11-21 |

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

## Similar variants {#similar}

Related CPSF2 variant pages (same residue, condition, or type): [CPSF2 p.Arg105Gln](/variant/cpsf2-p-arg105gln), [CPSF2 p.Arg366Cys](/variant/cpsf2-p-arg366cys), [CPSF2 p.Arg366His](/variant/cpsf2-p-arg366his), [CPSF2 p.Arg449His](/variant/cpsf2-p-arg449his), [CPSF2 p.Arg534Gln](/variant/cpsf2-p-arg534gln), [CPSF2 p.Arg579His](/variant/cpsf2-p-arg579his), [CPSF2 p.Arg730Gln](/variant/cpsf2-p-arg730gln), [CPSF2 p.Arg751His](/variant/cpsf2-p-arg751his).

### 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 3076887). 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.*