Is PNKP p.Pro261= (c.783G>A) pathogenic?

PNKP p.Pro261= (c.783G>A) is classified Benign/Likely benign in PNKP (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-06-01). Rare (popmax 0.64%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PNKP p.Pro261= (c.783G>A)?

PNKP p.Pro261= (c.783G>A) is associated with Inborn genetic diseases, microcephaly, seizures, and developmental delay, developmental and epileptic encephalopathy, 12 (ClinVar).

How common is PNKP p.Pro261= (c.783G>A) in the general population?

PNKP p.Pro261= (c.783G>A) is rare (popmax 0.64%, nfe) (gnomAD).

PNKP p.Pro261=

c.783G>A · rs145307985 · VCV138712

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

rare (popmax 0.64%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -3.3
Overall
CADD	1.106	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.64% European (non-Finnish) · 7,361/1,150,492 alleles

Filtering AF 0.628% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.623%

Overall 0.511% 7,960/1,558,080 alleles · rare exomes 7,425/1,405,796 · genomes 535/152,284 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.64%	156
Remaining individualsnot grpmax-eligible	0.424%	236
Admixed American	0.329%	304
Middle Eastern	0.15%	665
African / African-American	0.1%	996
Ashkenazi Jewishnot grpmax-eligible	0.0732%	1,367
Finnishnot grpmax-eligible	0.0636%	1,571
South Asian	0.0366%	2,734

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.Pro261=
Coding: c.783G>A
MANE Select: NM_007254
dbSNP: rs145307985
Type: single nucleotide variant
Location: chr19:49863722 (GRCh38)
Gene constraint: LOEUF 1.527 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.06 · 2 PDB
Residue 261: the 'phosphatase' region

Full PNKP 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

Also linked: microcephaly, seizures, and developmental delay developmental and epileptic encephalopathy, 12

Similar variants

PNKP p.Pro261Leu 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-pro261 (accessed [today's date]).

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