# NM_005192.4(CDKN3):c.577C>T (p.Arg193Trp)

https://sugi.bio/variant/cdkn3-p-arg193trp

## Summary

**CDKN3 p.Arg193Trp (c.577C>T)** is classified **Uncertain significance** in CDKN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-11). AlphaMissense: ambiguous (0.378); Very rare (popmax 0.00224%, eas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00224%, eas)

## For patients & families {#patients}

This is a change in the CDKN3 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 | [CDKN3](https://sugi.bio/atlas/gene/CDKN3/) |
| Protein change (HGVS p.) | p.Arg193Trp |
| Coding change (HGVS c.) | c.577C>T |
| MANE Select transcript | [NM_005192](https://www.ncbi.nlm.nih.gov/nuccore/NM_005192) |
| Variant type | single nucleotide variant |
| Location | chr14:54420016-54420016 (GRCh38) |
| ClinVar | [VCV3489703](https://www.ncbi.nlm.nih.gov/clinvar/variation/3489703/) |

**All HGVS expressions:** `NC_000014.8:g.54886734C>T`, `NC_000014.9:g.54420016C>T`, `NG_023235.1:g.28062C>T`, `NM_001130851.2:c.457C>T`, `NM_001330173.2:c.*58C>T`, `NM_005192.4:c.577C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.378) — no call either way
- REVEL 0.408 (indeterminate)
- SaProt LLR -14.192 (damaging)
- Conservation: phyloP 7.504, GERP 2.79, phastCons 1 — highly conserved
- CADD: **PHRED 33.0**. 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 0.76** across the covering region of the MANE Select transcript (54,397,069–54,420,075), spanning 23,006 bp. Chi-square p 0.00012. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.43 acceptor loss), 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.*
- Pangolin: Δ**0.31** (loss), gain 0.00 / loss 0.31. SpliceAI below 0.2. 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 **0.00224%** (eas) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/44,704 in the highest group · 3/1,455,960 alleles overall — very rare (popmax 0.00224%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00224% | 44,704 |
| European (non-Finnish) | 0.00017% | 587,527 |

*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}

**CDKN3** population constraint: LOEUF 1.123, pLI 0.38791, missense-Z 1.1129. *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 **193** lies in the tyrosine-protein phosphatase domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 91.18, 83% of residues very-high.

**2 experimental structure(s)** (PDB): [1FPZ](https://www.rcsb.org/structure/1FPZ), [1FQ1](https://www.rcsb.org/structure/1FQ1).

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

*Describes the biological roles of CDKN3 (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:** CDKN3's established molecular role includes protein serine/threonine phosphatase activity. p.Arg193Trp falls in the tyrosine-protein phosphatase domain.


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

**Molecular function:** protein serine/threonine phosphatase activity, protein tyrosine phosphatase activity.

**Biological process:** regulation of cell cycle.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-09-11.

**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 | 2024-09-11 |

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

## Similar variants {#similar}

Related CDKN3 variant pages (same residue, condition, or type): [CDKN3 p.Ala179Thr](/variant/cdkn3-p-ala179thr), [CDKN3 p.Asn91Lys](/variant/cdkn3-p-asn91lys), [CDKN3 p.Gln166His](/variant/cdkn3-p-gln166his), [CDKN3 p.Glu124Gly](/variant/cdkn3-p-glu124gly), [CDKN3 p.Glu125Asp](/variant/cdkn3-p-glu125asp), [CDKN3 p.Ile29Met](/variant/cdkn3-p-ile29met), [CDKN3 p.Ile75Met](/variant/cdkn3-p-ile75met), [CDKN3 p.Ile7Met](/variant/cdkn3-p-ile7met).

### 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 3489703). 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.*