Is PNKP p.Phe321= (c.963C>T) pathogenic?

PNKP p.Phe321= (c.963C>T) is classified Likely benign in PNKP (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-16). Very rare (popmax 0.000772%, nfe); Associated with developmental and epileptic encephalopathy, 12.

What condition is associated with PNKP p.Phe321= (c.963C>T)?

PNKP p.Phe321= (c.963C>T) is associated with developmental and epileptic encephalopathy, 12 (ClinVar).

How common is PNKP p.Phe321= (c.963C>T) in the general population?

PNKP p.Phe321= (c.963C>T) is very rare (popmax 0.000772%, nfe) (gnomAD).

PNKP p.Phe321=

Q: How is Epilepsy of infancy with migrating focal seizures inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.963C>T · rs1042120334 · VCV1128092

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000772%, nfe)

Conditions

developmental and epileptic encephalopathy, 12

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.46 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.29	GERP 0.62, phastCons 0.007
Overall
CADD	5.998	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000772% European (non-Finnish) · 9/1,165,958 alleles

Filtering AF 0.000363% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000263%

Overall 0.000568% 9/1,585,822 alleles · very rare exomes 9/1,433,544 · genomes 0/152,278 · 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: PNKP
Protein: p.Phe321=
Coding: c.963C>T
MANE Select: NM_007254
dbSNP: rs1042120334
Type: single nucleotide variant
Location: chr19:49862437 (GRCh38)
Gene constraint: LOEUF 1.527 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.06 · 2 PDB
Residue 321: the 'phosphatase' region

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

Disease context

developmental and epileptic encephalopathy, 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Epilepsy of infancy with migrating focal seizures (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

PNKP p.Phe321Leu Uncertain significance ★ ⚠ same residue
PNKP c.1126+1G>C Pathogenic/Likely pathogenic ★★ same condition
PNKP c.1188+1G>A Likely pathogenic ★★ same condition
PNKP c.1386+1G>C Pathogenic/Likely pathogenic ★★ same condition
PNKP c.636+1G>T Pathogenic/Likely pathogenic ★★ same condition
PNKP c.865+1G>A Likely pathogenic ★★ same condition
PNKP p.Arg204Ter Pathogenic/Likely pathogenic ★★ same condition
PNKP p.Arg439Ter Pathogenic ★★ 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/pnkp-p-phe321 (accessed [today's date]).

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