Is PNKD p.Pro58= (c.174G>T) pathogenic?

PNKD p.Pro58= (c.174G>T) is classified Likely benign in PNKD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-22). Very rare (popmax 0.000424%, nfe); Associated with paroxysmal nonkinesigenic dyskinesia.

What condition is associated with PNKD p.Pro58= (c.174G>T)?

PNKD p.Pro58= (c.174G>T) is associated with paroxysmal nonkinesigenic dyskinesia (ClinVar).

How common is PNKD p.Pro58= (c.174G>T) in the general population?

PNKD p.Pro58= (c.174G>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

How is Paroxysmal non-kinesigenic dyskinesia inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

PNKD p.Pro58=

c.174G>T · rs1427711767 · VCV1595110

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

paroxysmal nonkinesigenic dyskinesia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -4.1	GERP -3.9
Overall
CADD	5.558	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,018 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,020 alleles · very rare exomes 4/1,461,870 · genomes 1/152,150 · joint denominator

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: PNKD
Protein: p.Pro58=
Coding: c.174G>T
MANE Select: NM_015488
dbSNP: rs1427711767
Type: single nucleotide variant
Location: chr2:218271487 (GRCh38)
Gene constraint: LOEUF 1.131 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.69
Residue 58: the 'disordered' region

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

Disease context

paroxysmal nonkinesigenic dyskinesia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Paroxysmal non-kinesigenic dyskinesia (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

PNKD p.Pro58Leu Uncertain significance ★ ⚠ same residue
PNKD p.Pro58Ala Uncertain significance ★ ⚠ same residue
PNKD c.465+3G>A Uncertain significance ★★ same condition
PNKD p.Ala167Thr Uncertain significance ★★ ⚠ same condition
PNKD p.Ala28Gly Uncertain significance ★★ ⚠ same condition
PNKD p.Ala78Val Uncertain significance ★★ ⚠ same condition
PNKD p.Arg368Gln Uncertain significance ★★ ⚠ same condition
PNKD p.Asp365Val 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/pnkd-p-pro58 (accessed [today's date]).

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