# NM_001239.4(CCNH):c.261C>T (p.Phe87=)

https://sugi.bio/variant/ccnh-p-phe87

## Summary

**CCNH p.Phe87= (c.261C>T)** is classified **Likely benign** in CCNH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-20). Rare (popmax 0.895%, amr).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs191853622 · 2 submitters · rare (popmax 0.895%, amr)

## For patients & families {#patients}

This is a change in the CCNH gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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 | [CCNH](https://sugi.bio/atlas/gene/CCNH/) |
| Protein change (HGVS p.) | p.Phe87= |
| Coding change (HGVS c.) | c.261C>T |
| MANE Select transcript | [NM_001239](https://www.ncbi.nlm.nih.gov/nuccore/NM_001239) |
| dbSNP | [rs191853622](https://www.ncbi.nlm.nih.gov/snp/rs191853622/) |
| Variant type | single nucleotide variant |
| Location | chr5:87409343-87409343 (GRCh38) |
| ClinVar | [VCV733117](https://www.ncbi.nlm.nih.gov/clinvar/variation/733117/) |

**All HGVS expressions:** `NC_000005.10:g.87409343G>A`, `NC_000005.9:g.86705160G>A`, `NM_001199189.2:c.102C>T`, `NM_001239.4:c.261C>T`, `NM_001363539.2:c.261C>T`, `NM_001364075.2:c.261C>T`, `NM_001364076.2:c.102C>T`, `NR_157068.2:n.640C>T`, `NR_157069.2:n.397C>T`, `NR_157070.2:n.397C>T`, `NR_157071.2:n.397C>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 6.74, GERP 2.72, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.45**. 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: **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.
- Pangolin: Δ**0.28** (loss), gain 0.00 / loss 0.28. Not in the SpliceAI release. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.895%** (amr) · FAF95 0.831% · FAF99 0.806% · 512/57,176 in the highest group · 545/1,559,074 alleles overall — rare (popmax 0.895%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.895% | 112 |
| Remaining individuals (not grpmax-eligible) | 0.0248% | 4,039 |
| African / African-American | 0.00949% | 10,533 |
| East Asian | 0.00457% | 21,898 |
| South Asian | 0.00113% | 88,862 |
| European (non-Finnish) | 0.000704% | 142,098 |

*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}

**CCNH** population constraint: LOEUF 1.05, pLI 7.4251e-05, missense-Z 0.5227. *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 **87** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 86.26, 70% of residues very-high.

**49 experimental structure(s)** (PDB): [1JKW](https://www.rcsb.org/structure/1JKW), [1KXU](https://www.rcsb.org/structure/1KXU), [6O9L](https://www.rcsb.org/structure/6O9L), [6XBZ](https://www.rcsb.org/structure/6XBZ), [6XD3](https://www.rcsb.org/structure/6XD3), [7B5O](https://www.rcsb.org/structure/7B5O) — incl. mutant structure 9HIX.

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

*Describes the biological roles of CCNH (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:** CCNH participates in disease-associated pathways. In Reactome, CCNH is annotated in disease pathway(s) including **Formation of HIV elongation complex in the absence of HIV Tat**, **Formation of HIV-1 elongation complex containing HIV-1 Tat**.

**Disease mechanism (Reactome):** CCNH loss or alteration is curated in [Formation of HIV elongation complex in the absence of HIV Tat](https://reactome.org/content/detail/R-HSA-167152), [Formation of HIV-1 elongation complex containing HIV-1 Tat](https://reactome.org/content/detail/R-HSA-167200), [Formation of the HIV-1 Early Elongation Complex](https://reactome.org/content/detail/R-HSA-167158).

### Pathways affected {#pathways}

CCNH participates in **33 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Formation of HIV elongation complex in the absence of HIV Tat](https://reactome.org/content/detail/R-HSA-167152) | electronic |
| ⚕ [Formation of HIV-1 elongation complex containing HIV-1 Tat](https://reactome.org/content/detail/R-HSA-167200) | electronic |
| ⚕ [Formation of the HIV-1 Early Elongation Complex](https://reactome.org/content/detail/R-HSA-167158) | electronic |
| ⚕ [HIV Transcription Initiation](https://reactome.org/content/detail/R-HSA-167161) | electronic |
| ⚕ [RNA Pol II CTD phosphorylation and interaction with CE during HIV infection](https://reactome.org/content/detail/R-HSA-167160) | electronic |
| ⚕ [RNA Polymerase II HIV Promoter Escape](https://reactome.org/content/detail/R-HSA-167162) | electronic |
| ⚕ [Tat-mediated elongation of the HIV-1 transcript](https://reactome.org/content/detail/R-HSA-167246) | electronic |
| ⚕ [Transcription of the HIV genome](https://reactome.org/content/detail/R-HSA-167172) | electronic |
| [Cyclin A/B1/B2 associated events during G2/M transition](https://reactome.org/content/detail/R-HSA-69273) | curated |
| [Cyclin A:Cdk2-associated events at S phase entry](https://reactome.org/content/detail/R-HSA-69656) | curated |
| [Cyclin D associated events in G1](https://reactome.org/content/detail/R-HSA-69231) | curated |
| [Cyclin E associated events during G1/S transition ](https://reactome.org/content/detail/R-HSA-69202) | curated |
| [Dual incision in TC-NER](https://reactome.org/content/detail/R-HSA-6782135) | curated |
| [Formation of Incision Complex in GG-NER](https://reactome.org/content/detail/R-HSA-5696395) | curated |
| [Formation of RNA Pol II elongation complex ](https://reactome.org/content/detail/R-HSA-112382) | curated |
| [Formation of TC-NER Pre-Incision Complex](https://reactome.org/content/detail/R-HSA-6781823) | curated |
| [Formation of the Early Elongation Complex](https://reactome.org/content/detail/R-HSA-113418) | curated |
| [Gap-filling DNA repair synthesis and ligation in TC-NER](https://reactome.org/content/detail/R-HSA-6782210) | curated |
| [RNA Pol II CTD phosphorylation and interaction with CE](https://reactome.org/content/detail/R-HSA-77075) | curated |
| [RNA Polymerase I Promoter Escape](https://reactome.org/content/detail/R-HSA-73772) | curated |
| [RNA Polymerase I Transcription Initiation](https://reactome.org/content/detail/R-HSA-73762) | curated |
| [RNA Polymerase II Pre-transcription Events](https://reactome.org/content/detail/R-HSA-674695) | curated |
| [RNA Polymerase II Promoter Escape](https://reactome.org/content/detail/R-HSA-73776) | curated |
| [RNA Polymerase II Transcription Elongation](https://reactome.org/content/detail/R-HSA-75955) | curated |
| [RNA Polymerase II Transcription Initiation](https://reactome.org/content/detail/R-HSA-75953) | curated |
| [RNA Polymerase II Transcription Initiation And Promoter Clearance](https://reactome.org/content/detail/R-HSA-76042) | curated |
| [RNA Polymerase II Transcription Pre-Initiation And Promoter Opening](https://reactome.org/content/detail/R-HSA-73779) | curated |
| [RUNX1 regulates transcription of genes involved in differentiation of HSCs](https://reactome.org/content/detail/R-HSA-8939236) | curated |
| [TP53 Regulates Transcription of DNA Repair Genes](https://reactome.org/content/detail/R-HSA-6796648) | curated |
| [Transcription-Coupled Nucleotide Excision Repair (TC-NER)](https://reactome.org/content/detail/R-HSA-6781827) | curated |
| [mRNA Capping](https://reactome.org/content/detail/R-HSA-72086) | curated |
| [NoRC negatively regulates rRNA expression](https://reactome.org/content/detail/R-HSA-427413) | electronic |
| [RNA Polymerase I Transcription Termination](https://reactome.org/content/detail/R-HSA-73863) | electronic |

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

**Biological process:** regulation of transcription by RNA polymerase II, transcription initiation at RNA polymerase II promoter, protein stabilization, regulation of G1/S transition of mitotic cell cycle.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2018-06-20.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2018); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2018-06-20 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related CCNH variant pages (same residue, condition, or type): [RASA1 c.1698+1G>A](/variant/rasa1-c-1698-plus-1g-a), [RASA1 c.2012-2A>G](/variant/rasa1-c-2012-minus-2a-g), [RASA1 c.2603+1G>A](/variant/rasa1-c-2603-plus-1g-a), [RASA1 c.2691-1G>T](/variant/rasa1-c-2691-minus-1g-t), [RASA1 c.2925+1G>T](/variant/rasa1-c-2925-plus-1g-t), [RASA1 c.899+1G>T](/variant/rasa1-c-899-plus-1g-t), [RASA1 p.Arg1010Ter](/variant/rasa1-p-arg1010ter), [RASA1 p.Arg285Ter](/variant/rasa1-p-arg285ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 733117). 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.*