# NM_006201.5(CDK16):c.47G>A (p.Arg16Gln)

https://sugi.bio/variant/cdk16-p-arg16gln

## Summary

**CDK16 p.Arg16Gln (c.47G>A)** is classified **Uncertain significance** in CDK16 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.7365); Ultra-rare (popmax 0.0178%, eas); Associated with oligospermia.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0178%, eas)

## For patients & families {#patients}

This is a change in the CDK16 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to oligospermia.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 27 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDK16](https://sugi.bio/atlas/gene/CDK16/) |
| Protein change (HGVS p.) | p.Arg16Gln |
| Coding change (HGVS c.) | c.47G>A |
| MANE Select transcript | [NM_006201](https://www.ncbi.nlm.nih.gov/nuccore/NM_006201) |
| Variant type | single nucleotide variant |
| Location | chrX:47223604-47223604 (GRCh38) |
| ClinVar | [VCV3239640](https://www.ncbi.nlm.nih.gov/clinvar/variation/3239640/) |

**All HGVS expressions:** `NC_000023.10:g.47083003G>A`, `NC_000023.11:g.47223604G>A`, `NG_012517.2:g.10476G>A`, `NM_001170460.2:c.269G>A`, `NM_006201.5:c.47G>A`, `NM_033018.4:c.65G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7365)
- REVEL 0.259 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -7.466 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP 11.736, GERP 1.41, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 23.3**. 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 0.69** across the covering region of the MANE Select transcript (47,223,558–47,224,512), spanning 954 bp. Chi-square p 0.002. 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 **0.0178%** (eas) · FAF95 0.00766% · FAF99 0.00527% · 6/33,733 in the highest group · 17/1,209,714 alleles overall — ultra-rare (popmax 0.0178%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0178% | 5,622 |
| South Asian | 0.00528% | 18,939 |
| Admixed American | 0.00436% | 22,918 |
| European (non-Finnish) | 0.00067% | 149,148 |

*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}


Curated gene–disease validity (ClinGen):

- **X-linked complex neurodevelopmental disorder** — Limited (XL)

## Protein context {#protein}

Residue **16** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 72.92, 46% of residues very-high.

**3 experimental structure(s)** (PDB): [3MTL](https://www.rcsb.org/structure/3MTL), [5G6V](https://www.rcsb.org/structure/5G6V), [9R2I](https://www.rcsb.org/structure/9R2I).

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

*Describes the biological roles of CDK16 (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:** CDK16's established molecular role includes protein serine/threonine kinase activity. p.Arg16Gln falls in the disordered region.


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

**Molecular function:** protein serine/threonine kinase activity.

**Biological process:** positive regulation of autophagy, regulation of insulin secretion involved in cellular response to glucose stimulus.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Huzhibin Lab, Nanjing Medical University | Uncertain significance | criteria provided, single submitter | research |  |

## Associated conditions {#conditions}

[oligospermia](https://sugi.bio/atlas/disease/oligospermia/).

**Reported phenotype names (ClinVar):** Oligospermia, Abnormal sperm morphology, Reduced sperm motility, asthenozoospermia, Teratozoospermia.

## Similar variants {#similar}

Related CDK16 variant pages (same residue, condition, or type): [CDK16 p.Leu15Phe](/variant/cdk16-p-leu15phe), [CDK16 c.1376-10C>T](/variant/cdk16-c-1376-minus-10c-t), [CDK16 c.793-5C>T](/variant/cdk16-c-793-minus-5c-t), [CDK16 c.-6-279C>T](/variant/cdk16-c-minus-6-minus-279c-t), [CDK16 p.Gly347=](/variant/cdk16-p-gly347), [CDK16 c.-5T>G](/variant/cdk16-c-minus-5t-g), [CDK16 c.-6-245C>T](/variant/cdk16-c-minus-6-minus-245c-t), [CDK16 c.-6-264A>G](/variant/cdk16-c-minus-6-minus-264a-g).

### 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 3239640). 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.*