# NM_017525.3(CDC42BPG):c.1037C>T (p.Ala346Val)

https://sugi.bio/variant/cdc42bpg-p-ala346val

## Summary

**CDC42BPG p.Ala346Val (c.1037C>T)** is classified **Uncertain significance** in CDC42BPG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely benign (0.1071); Very rare (popmax 0.0039%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs146881257 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.0039%, nfe)

## For patients & families {#patients}

This is a change in the CDC42BPG 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 | [CDC42BPG](https://sugi.bio/atlas/gene/CDC42BPG/) |
| Protein change (HGVS p.) | p.Ala346Val |
| Coding change (HGVS c.) | c.1037C>T |
| MANE Select transcript | [NM_017525](https://www.ncbi.nlm.nih.gov/nuccore/NM_017525) |
| dbSNP | [rs146881257](https://www.ncbi.nlm.nih.gov/snp/rs146881257/) |
| Variant type | single nucleotide variant |
| Location | chr11:64838742-64838742 (GRCh38) |
| ClinVar | [VCV2225198](https://www.ncbi.nlm.nih.gov/clinvar/variation/2225198/) |

**All HGVS expressions:** `NC_000011.10:g.64838742G>A`, `NC_000011.9:g.64606214G>A`, `NM_017525.3:c.1037C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1071)
- REVEL 0.062 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.698 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.47) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.568, GERP -3.64, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.1**. 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 0.90** across the covering region of the MANE Select transcript (64,827,691–64,844,569), spanning 16,878 bp. Chi-square p 1.2e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.47**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.47**.
- Population frequency (gnomAD v4.1): grpmax **0.0039%** (nfe) · FAF95 0.00299% · FAF99 0.00267% · 46/1,179,994 in the highest group · 51/1,612,504 alleles overall — very rare (popmax 0.0039%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0039% | 25,652 |
| Admixed American | 0.00333% | 30,001 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,219 |
| South Asian | 0.0011% | 91,092 |

*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}

**CDC42BPG** population constraint: LOEUF 1.039, pLI 3.8163e-46, missense-Z 0.04915. *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 **346** lies in the agc-kinase c-terminal domain.

AlphaFold model confidence (whole protein): pLDDT 72.90, 26% of residues very-high.

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

*Describes the biological roles of CDC42BPG (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:** CDC42BPG's established molecular role includes magnesium ion binding. p.Ala346Val falls in the agc-kinase c-terminal domain.


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

**Molecular function:** magnesium ion binding, protein serine/threonine kinase activity, ATP binding.

**Biological process:** protein phosphorylation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-13.

**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 | 2025-08-13 |

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

## Similar variants {#similar}

Related CDC42BPG variant pages (same residue, condition, or type): [CDC42BPG p.Ile77=](/variant/cdc42bpg-p-ile77), [CDC42BPG p.Lys467Asn](/variant/cdc42bpg-p-lys467asn), [CDC42BPG p.Pro1257=](/variant/cdc42bpg-p-pro1257), [CDC42BPG p.Ala1013Val](/variant/cdc42bpg-p-ala1013val), [CDC42BPG p.Ala1036Val](/variant/cdc42bpg-p-ala1036val), [CDC42BPG p.Ala1071Val](/variant/cdc42bpg-p-ala1071val), [CDC42BPG p.Ala1098Thr](/variant/cdc42bpg-p-ala1098thr), [CDC42BPG p.Ala1242Val](/variant/cdc42bpg-p-ala1242val).

### 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 2225198). 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.*