Is NEK8 p.Phe415= (c.1245C>T) pathogenic?

NEK8 p.Phe415= (c.1245C>T) is classified Likely benign in NEK8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-04). Very rare (popmax 0.00267%, afr); Associated with nephronophthisis 9.

What condition is associated with NEK8 p.Phe415= (c.1245C>T)?

NEK8 p.Phe415= (c.1245C>T) is associated with nephronophthisis 9 (ClinVar).

How common is NEK8 p.Phe415= (c.1245C>T) in the general population?

NEK8 p.Phe415= (c.1245C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Nephronophthisis inherited?

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

NEK8 p.Phe415=

c.1245C>T · rs1373429777 · VCV2758624

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

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 -0.8	GERP -3.6, phastCons 0.024
Overall
CADD	6.466	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/75,046 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000434% 7/1,614,124 alleles · very rare exomes 7/1,461,782 · genomes 0/152,342 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,523
South Asian	0.0022%	45,541
European (non-Finnish)	0.000254%	393,317

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.Phe415=
Coding: c.1245C>T
MANE Select: NM_178170
dbSNP: rs1373429777
Type: single nucleotide variant
Location: chr17:28738693 (GRCh38)
Gene constraint: LOEUF 0.835 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.23
Residue 415: 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 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
NEK8 c.2050+1G>A 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/nek8-p-phe415 (accessed [today's date]).

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