Is WNK3 p.Gly1663Glu (c.4988G>A) pathogenic?

WNK3 p.Gly1663Glu (c.4988G>A) is classified Uncertain significance in WNK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-15). AlphaMissense: ambiguous (0.4215); Absent from gnomAD v4.1.

How common is WNK3 p.Gly1663Glu (c.4988G>A) in the general population?

WNK3 p.Gly1663Glu (c.4988G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about WNK3 p.Gly1663Glu (c.4988G>A)?

AlphaMissense predicts ambiguous (score 0.4215) — an in-silico prediction, not a clinical call.

WNK3 p.Gly1663Glu

c.4988G>A · rs2520024601 · VCV2526026

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4215 · 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	0.4215	ambiguous
REVEL	0.23	benign-leaning
SaProt	LLR -6.32	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 96 kb · p 6.9e-06 · regional, not allelic
Overall
CADD	23.1	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.Gly1663Glu
Coding: c.4988G>A
MANE Select: NM_020922
dbSNP: rs2520024601
Type: single nucleotide variant
Location: chrX:54202076 (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.Gly1663Arg 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-gly1663glu (accessed [today's date]).

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