# NM_020922.5(WNK3):c.4987G>A (p.Gly1663Arg)

https://sugi.bio/variant/wnk3-p-gly1663arg

## Summary

**WNK3 p.Gly1663Arg (c.4987G>A)** is classified **Uncertain significance** in WNK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: ambiguous (0.5027); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the WNK3 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 | [WNK3](https://sugi.bio/atlas/gene/WNK3/) |
| Protein change (HGVS p.) | p.Gly1663Arg |
| Coding change (HGVS c.) | c.4987G>A |
| MANE Select transcript | [NM_020922](https://www.ncbi.nlm.nih.gov/nuccore/NM_020922) |
| Variant type | single nucleotide variant |
| Location | chrX:54202077-54202077 (GRCh38) |
| ClinVar | [VCV4087971](https://www.ncbi.nlm.nih.gov/clinvar/variation/4087971/) |

**All HGVS expressions:** `NC_000023.10:g.54228510C>T`, `NC_000023.11:g.54202077C>T`, `NG_021259.2:g.160929G>A`, `NM_001002838.4:c.4816G>A`, `NM_001395166.1:c.4816G>A`, `NM_020922.5:c.4987G>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.5027) — no call either way
- REVEL 0.212 (benign-leaning)
- SaProt LLR -7.018 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate
- SpliceAI predicts **donor gain** (Δ 0.66) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.819, GERP 0.438, phastCons 1 — highly conserved
- CADD: **PHRED 29.1**. 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 0.86** across the covering region of the MANE Select transcript (54,198,327–54,294,796), spanning 96,469 bp. Chi-square p 6.9e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.66**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.66**.
- Pangolin: Δ**0.20** (gain), gain 0.20 / loss 0.00. Agrees with SpliceAI. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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.*

## Protein context {#protein}

Residue **1663** lies in a UniProt-annotated variant site (in prs; likely pathogenic).

AlphaFold model confidence (whole protein): pLDDT 48.31, 14% of residues very-high.

**9 experimental structure(s)** (PDB): [5NKP](https://www.rcsb.org/structure/5NKP), [5O1V](https://www.rcsb.org/structure/5O1V), [5O21](https://www.rcsb.org/structure/5O21), [5O23](https://www.rcsb.org/structure/5O23), [5O26](https://www.rcsb.org/structure/5O26), [5O2B](https://www.rcsb.org/structure/5O2B).

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

*Describes the biological roles of WNK3 (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:** WNK3's established molecular role includes protein kinase activity.


### Pathways affected {#pathways}

WNK3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Stimuli-sensing channels](https://reactome.org/content/detail/R-HSA-2672351) | curated |

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

**Molecular function:** protein kinase activity, protein serine/threonine kinase activity, transmembrane transporter binding, molecular condensate scaffold activity, transporter activator activity.

**Biological process:** cell volume homeostasis, osmosensory signaling pathway, positive regulation of sodium ion transport, positive regulation of peptidyl-threonine phosphorylation, negative regulation of apoptotic process, monoatomic ion homeostasis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-26.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-26 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related WNK3 variant pages (same residue, condition, or type): [WNK3 p.Gly1663Glu](/variant/wnk3-p-gly1663glu), [WNK3 p.Ala827Asp](/variant/wnk3-p-ala827asp), [WNK3 p.Ala998Gly](/variant/wnk3-p-ala998gly), [WNK3 p.Arg1599His](/variant/wnk3-p-arg1599his), [WNK3 p.Arg487Trp](/variant/wnk3-p-arg487trp), [WNK3 p.Gln956Leu](/variant/wnk3-p-gln956leu), [WNK3 p.Ile1355Thr](/variant/wnk3-p-ile1355thr), [WNK3 p.Pro1725Leu](/variant/wnk3-p-pro1725leu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 4087971). 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.*