# NM_033331.4(CDC14B):c.745A>G (p.Ile249Val)

https://sugi.bio/variant/cdc14b-p-ile249val

## Summary

**CDC14B p.Ile249Val (c.745A>G)** is classified **Uncertain significance** in CDC14B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely benign (0.0884); Very rare (popmax 0.00268%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00268%, afr)

## For patients & families {#patients}

This is a change in the CDC14B 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 | [CDC14B](https://sugi.bio/atlas/gene/CDC14B/) |
| Protein change (HGVS p.) | p.Ile249Val |
| Coding change (HGVS c.) | c.745A>G |
| MANE Select transcript | [NM_033331](https://www.ncbi.nlm.nih.gov/nuccore/NM_033331) |
| Variant type | single nucleotide variant |
| Location | chr9:96534128-96534128 (GRCh38) |
| ClinVar | [VCV4650793](https://www.ncbi.nlm.nih.gov/clinvar/variation/4650793/) |

**All HGVS expressions:** `NC_000009.11:g.99296410T>C`, `NC_000009.12:g.96534128T>C`, `NM_001077181.3:c.634A>G`, `NM_001351567.3:c.745A>G`, `NM_001351568.3:c.634A>G`, `NM_001351569.2:c.634A>G`, `NM_001351570.1:c.676A>G`, `NM_003671.5:c.745A>G`, `NM_033331.4:c.745A>G`, `NR_147239.2:n.1210A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0884)
- REVEL 0.222 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.279 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.233, GERP 0.811, phastCons 0.997 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 18.7**. 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 0.79** across the covering region of the MANE Select transcript (96,503,756–96,619,378), spanning 115,622 bp. Chi-square p 1.5e-07. 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 (T>A, Δ0.24 acceptor gain), 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.*
- Population frequency (gnomAD v4.1): grpmax **0.00268%** (afr) · FAF95 0.000444% · FAF99 0.000166% · 2/74,750 in the highest group · 3/1,608,208 alleles overall — very rare (popmax 0.00268%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00268% | 37,375 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,256 |

*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}

**CDC14B** population constraint: LOEUF 0.526, pLI 0.95893, missense-Z 0.80763. *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 **249** lies in the tyrosine-protein phosphatase domain; an α-helix; the 'b' region.

AlphaFold model confidence (whole protein): pLDDT 81.04, 64% of residues very-high.

**3 experimental structure(s)** (PDB): [1OHC](https://www.rcsb.org/structure/1OHC), [1OHD](https://www.rcsb.org/structure/1OHD), [1OHE](https://www.rcsb.org/structure/1OHE).

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

*Describes the biological roles of CDC14B (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:** CDC14B's established molecular role includes protein serine/threonine phosphatase activity. p.Ile249Val falls in the tyrosine-protein phosphatase domain.


### Pathways affected {#pathways}

CDC14B participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [MAPK6/MAPK4 signaling](https://reactome.org/content/detail/R-HSA-5687128) | curated |

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

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

**Biological process:** protein dephosphorylation, mitotic G2 DNA damage checkpoint signaling, positive regulation of ubiquitin protein ligase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-24.

**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 | 2025-11-24 |

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

## Similar variants {#similar}

Related CDC14B variant pages (same residue, condition, or type): [CDC14B p.Ala13Thr](/variant/cdc14b-p-ala13thr), [CDC14B p.Ala13Val](/variant/cdc14b-p-ala13val), [CDC14B p.Ala14Ser](/variant/cdc14b-p-ala14ser), [CDC14B p.Ala286Val](/variant/cdc14b-p-ala286val), [CDC14B p.Ala388Val](/variant/cdc14b-p-ala388val), [CDC14B p.Ala87Thr](/variant/cdc14b-p-ala87thr), [CDC14B p.Ala95Val](/variant/cdc14b-p-ala95val), [CDC14B p.Arg266Lys](/variant/cdc14b-p-arg266lys).

### 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 4650793). 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.*