# NM_001799.4(CDK7):c.485T>C (p.Phe162Ser)

https://sugi.bio/variant/cdk7-p-phe162ser

## Summary

**CDK7 p.Phe162Ser (c.485T>C)** is classified **Uncertain significance** in CDK7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-24). AlphaMissense: likely pathogenic (0.9759); Very rare (popmax 0.00267%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs771273531 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the CDK7 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 | [CDK7](https://sugi.bio/atlas/gene/CDK7/) |
| Protein change (HGVS p.) | p.Phe162Ser |
| Coding change (HGVS c.) | c.485T>C |
| MANE Select transcript | [NM_001799](https://www.ncbi.nlm.nih.gov/nuccore/NM_001799) |
| dbSNP | [rs771273531](https://www.ncbi.nlm.nih.gov/snp/rs771273531/) |
| Variant type | single nucleotide variant |
| Location | chr5:69259894-69259894 (GRCh38) |
| ClinVar | [VCV2551928](https://www.ncbi.nlm.nih.gov/clinvar/variation/2551928/) |

**All HGVS expressions:** `NC_000005.10:g.69259894T>C`, `NC_000005.9:g.68555721T>C`, `NM_001324069.2:c.362T>C`, `NM_001324070.2:c.314T>C`, `NM_001324071.2:c.314T>C`, `NM_001324072.1:c.206T>C`, `NM_001324074.2:c.206T>C`, `NM_001324075.2:c.206T>C`, `NM_001324077.1:c.206T>C`, `NM_001324078.2:c.206T>C`, `NM_001799.4:c.485T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9759)
- REVEL 0.783 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.372 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.867, GERP 1.93, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 31.0**. 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 0.77** across the covering region of the MANE Select transcript (69,234,976–69,277,132), spanning 42,156 bp. Chi-square p 2.4e-06. 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 (gnomAD v4.1): grpmax **0.00267%** (afr) · FAF95 0.000443% · FAF99 0.000166% · 2/74,930 in the highest group · 7/1,613,830 alleles overall — very rare (popmax 0.00267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,242 |
| African / African-American (grpmax) | 0.00267% | 37,465 |
| South Asian | 0.0022% | 45,539 |
| European (non-Finnish) | 8.48e-05% | 1,179,823 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CDK7** population constraint: LOEUF 0.774, pLI 0.30573, missense-Z 0.83974. *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 **162** lies in the protein kinase domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 82.29, 62% of residues very-high.

**56 experimental structure(s)** (PDB): [1UA2](https://www.rcsb.org/structure/1UA2), [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), [7B5Q](https://www.rcsb.org/structure/7B5Q) — incl. mutant structure 9HIX.

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

*Describes the biological roles of CDK7 (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:** CDK7's established molecular role includes ATP-dependent activity, acting on DNA. p.Phe162Ser falls in the protein kinase domain. In Reactome, CDK7 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):** CDK7 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}

CDK7 participates in **34 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 |
| [RNA polymerase II transcribes snRNA genes](https://reactome.org/content/detail/R-HSA-6807505) | electronic |

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

**Molecular function:** ATP-dependent activity, acting on DNA, RNA polymerase II CTD heptapeptide repeat kinase activity, RNA polymerase II CTD heptapeptide repeat S5 kinase activity.

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

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-24.

**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 | 2023-05-24 |

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

## Similar variants {#similar}

Related CDK7 variant pages (same residue, condition, or type): [CDK7 p.Ala180Thr](/variant/cdk7-p-ala180thr), [CDK7 p.Arg11Leu](/variant/cdk7-p-arg11leu), [CDK7 p.Arg11Ser](/variant/cdk7-p-arg11ser), [CDK7 p.Asn35Tyr](/variant/cdk7-p-asn35tyr), [CDK7 p.Asn86Asp](/variant/cdk7-p-asn86asp), [CDK7 p.Asp104Gly](/variant/cdk7-p-asp104gly), [CDK7 p.Asp146Glu](/variant/cdk7-p-asp146glu), [CDK7 p.Asp267Asn](/variant/cdk7-p-asp267asn).

### 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 2551928). 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.*