Is NEK8 p.Pro256= (c.768C>G) pathogenic?

NEK8 p.Pro256= (c.768C>G) is classified Likely benign in NEK8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-03). Very rare (popmax 0.00167%, amr); Associated with nephronophthisis 9.

What condition is associated with NEK8 p.Pro256= (c.768C>G)?

NEK8 p.Pro256= (c.768C>G) is associated with nephronophthisis 9 (ClinVar).

How common is NEK8 p.Pro256= (c.768C>G) in the general population?

NEK8 p.Pro256= (c.768C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Nephronophthisis inherited?

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

NEK8 p.Pro256=

c.768C>G · rs761378547 · VCV2086334

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

nephronophthisis 9

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 -0.52	GERP -3.1, phastCons 0.028
Overall
CADD	9.252	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,028 alleles

Overall 6.2e-05% 1/1,613,156 alleles · very rare exomes 1/1,460,818 · genomes 0/152,338 · 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: NEK8
Protein: p.Pro256=
Coding: c.768C>G
MANE Select: NM_178170
dbSNP: rs761378547
Type: single nucleotide variant
Location: chr17:28737455 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.23
Residue 256: the protein kinase domain; a UniProt-annotated variant site (in rhpd2; likely pathogenic; loss of protein expression)

Full NEK8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephronophthisis 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

NEK8 p.Pro256Arg Uncertain significance ★★ ⚠ same residue
NEK8 c.1418-1G>A Pathogenic/Likely pathogenic ★★ same condition
NEK8 c.828-1G>C Pathogenic/Likely pathogenic ★★ same condition
NEK8 c.889+1G>T Likely pathogenic ★★ same condition
NEK8 p.Arg127Ter Pathogenic/Likely pathogenic ★★ same condition
NEK8 p.Arg499Ter Pathogenic/Likely pathogenic ★★ same condition
NEK8 p.Arg599Ter Pathogenic/Likely pathogenic ★★ same condition
NEK8 p.Glu444Ter Pathogenic/Likely 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/nek8-p-pro256 (accessed [today's date]).

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