Is NPHP1 p.Ile517fs (c.1551del) pathogenic?

NPHP1 p.Ile517fs (c.1551del) is classified Pathogenic in NPHP1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-03-10). Very rare (popmax 0.00145%, nfe); Associated with nephronophthisis.

What condition is associated with NPHP1 p.Ile517fs (c.1551del)?

NPHP1 p.Ile517fs (c.1551del) is associated with nephronophthisis, nephronophthisis 1, Senior-Loken syndrome 1 (ClinVar).

How common is NPHP1 p.Ile517fs (c.1551del) in the general population?

NPHP1 p.Ile517fs (c.1551del) is very rare (popmax 0.00145%, nfe) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP1 p.Ile517fs

c.1551del · rs1017750255 · VCV595558

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00145%, nfe)

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 17 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00145% European (non-Finnish) · 17/1,174,414 alleles

Filtering AF 0.000882% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000721%

Overall 0.00106% 17/1,607,610 alleles · very rare exomes 14/1,455,510 · genomes 3/152,100 · 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: NPHP1
Protein: p.Ile517fs
Coding: c.1551del
MANE Select: NM_001128178
dbSNP: rs1017750255
Type: Deletion
Location: chr2:110131770 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB

Full NPHP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: nephronophthisis 1 Senior-Loken syndrome 1 Joubert syndrome with renal defect Joubert syndrome and related disorders

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP1 c.141_143+40del Likely pathogenic ★★ same condition
NPHP1 p.Asn61fs Pathogenic/Likely pathogenic ★★ same condition
NPHP1 p.Asp162fs Pathogenic/Likely pathogenic ★★ same condition
NPHP1 p.Glu454fs Pathogenic ★★ same condition
NPHP1 p.Lys185fs Pathogenic ★★ same condition
NPHP1 p.Lys377fs Pathogenic ★★ same condition
NPHP1 p.Ser129fs Pathogenic/Likely pathogenic ★★ same condition
NPHP1 p.Ser29fs 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/nphp1-p-ile517fs (accessed [today's date]).

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