Is WNK3 p.Gly1663Arg (c.4987G>A) pathogenic?

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.

How common is WNK3 p.Gly1663Arg (c.4987G>A) in the general population?

WNK3 p.Gly1663Arg (c.4987G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about WNK3 p.Gly1663Arg (c.4987G>A)?

AlphaMissense predicts ambiguous (score 0.5027) — an in-silico prediction, not a clinical call.

WNK3 p.Gly1663Arg

c.4987G>A · VCV4087971

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5027 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5027	ambiguous
REVEL	0.212	benign-leaning
SaProt	LLR -7.02	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.66	donor gain · deltas
Pangolin	Δ0.20	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.8	GERP 0.44, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 96 kb · p 6.9e-06 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: WNK3
Protein: p.Gly1663Arg
Coding: c.4987G>A
MANE Select: NM_020922
Type: single nucleotide variant
Location: chrX:54202077 (GRCh38)
Structure: AlphaFold pLDDT 48.31 · 9 PDB
Residue 1663: a UniProt-annotated variant site (in prs; likely pathogenic)

Full WNK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

WNK3 p.Gly1663Glu Uncertain significance ★ ⚠ same residue
WNK3 p.Ala827Asp Uncertain significance ★★ ⚠ same type
WNK3 p.Ala998Gly Uncertain significance ★★ ⚠ same type
WNK3 p.Arg1599His Uncertain significance ★★ ⚠ same type
WNK3 p.Arg487Trp Uncertain significance ★★ ⚠ same type
WNK3 p.Gln956Leu Uncertain significance ★★ ⚠ same type
WNK3 p.Ile1355Thr Uncertain significance ★★ ⚠ same type
WNK3 p.Pro1725Leu Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/wnk3-p-gly1663arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown