Is WNK4 p.Arg464Pro (c.1391G>C) pathogenic?

WNK4 p.Arg464Pro (c.1391G>C) is classified Uncertain significance in WNK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-20). AlphaMissense: likely pathogenic (0.6353); Ultra-rare (popmax 0.054%, sas); Associated with Inborn genetic diseases.

What condition is associated with WNK4 p.Arg464Pro (c.1391G>C)?

WNK4 p.Arg464Pro (c.1391G>C) is associated with Inborn genetic diseases (ClinVar).

How common is WNK4 p.Arg464Pro (c.1391G>C) in the general population?

WNK4 p.Arg464Pro (c.1391G>C) is ultra-rare (popmax 0.054%, sas) (gnomAD).

What do computational predictors say about WNK4 p.Arg464Pro (c.1391G>C)?

AlphaMissense predicts likely pathogenic (score 0.6353) — an in-silico prediction, not a clinical call.

WNK4 p.Arg464Pro

c.1391G>C · rs570613650 · VCV2302803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6353 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.054%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6353	likely pathogenic
REVEL	0.275	benign-leaning
SaProt	LLR -7.79	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 0.71, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.027 · regional, not allelic
Overall
CADD	25.1	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

Grpmax group 0.054% South Asian · 47/87,084 alleles

Filtering AF 0.0417% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0373%

Overall 0.00316% 50/1,582,534 alleles · ultra-rare exomes 46/1,430,144 · genomes 4/152,390 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.054%	1,853
Remaining individualsnot grpmax-eligible	0.0049%	20,427

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: WNK4
Protein: p.Arg464Pro
Coding: c.1391G>C
MANE Select: NM_032387
dbSNP: rs570613650
Type: single nucleotide variant
Location: chr17:42785397 (GRCh38)
Gene constraint: LOEUF 0.929 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.38 · 3 PDB

Full WNK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

WNK4 p.Ala443Val Uncertain significance ★★ ⚠ same condition
WNK4 p.Ala50Thr Uncertain significance ★★ ⚠ same condition
WNK4 p.Ala574Ser Uncertain significance ★★ ⚠ same condition
WNK4 p.Arg1016Cys Uncertain significance ★★ ⚠ same condition
WNK4 p.Arg1142Gln Uncertain significance ★★ ⚠ same condition
WNK4 p.Arg1187Cys Uncertain significance ★★ ⚠ same condition
WNK4 p.Arg1199Cys Uncertain significance ★★ same condition
WNK4 p.Arg1199His Uncertain significance ★★ same condition

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/wnk4-p-arg464pro (accessed [today's date]).

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