Is NPHP1 p.Lys185fs (c.555del) pathogenic?

NPHP1 p.Lys185fs (c.555del) is classified Pathogenic in NPHP1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-11). Very rare (popmax 0.00668%, amr); Associated with nephronophthisis.

What condition is associated with NPHP1 p.Lys185fs (c.555del)?

NPHP1 p.Lys185fs (c.555del) is associated with nephronophthisis, Joubert syndrome with renal defect (ClinVar).

How common is NPHP1 p.Lys185fs (c.555del) in the general population?

NPHP1 p.Lys185fs (c.555del) is very rare (popmax 0.00668%, amr) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP1 p.Lys185fs

c.555del · rs766524637 · VCV638899

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00668%, amr)

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 6 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.4	GERP -0.8, phastCons 1
Overall
CADD	23.4	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 0.00668% Admixed American · 4/59,904 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00124% 20/1,611,110 alleles · very rare exomes 17/1,459,742 · genomes 3/151,368 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00668%	14,976
Finnishnot grpmax-eligible	0.00157%	63,802
European (non-Finnish)	0.00119%	84,152
South Asian	0.0011%	90,974

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.Lys185fs
Coding: c.555del
MANE Select: NM_001128178
dbSNP: rs766524637
Type: Deletion
Location: chr2:110168521 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB
Residue 185: the sh3 domain

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: Joubert syndrome with renal defect

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP1 p.Lys185= Conflicting classifications of pathogenicity ★ same residue
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.Ile517fs Pathogenic ★★ same condition
NPHP1 p.Lys377fs Pathogenic ★★ same condition
NPHP1 p.Ser129fs 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/nphp1-p-lys185fs (accessed [today's date]).

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