Is NPHP1 p.Pro186fs (c.555dup) pathogenic?

NPHP1 p.Pro186fs (c.555dup) is classified Pathogenic in NPHP1 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-01-17). Very rare (popmax 0.00807%, nfe); Associated with NPHP1-related disorder.

What condition is associated with NPHP1 p.Pro186fs (c.555dup)?

NPHP1 p.Pro186fs (c.555dup) is associated with NPHP1-related disorder, nephronophthisis 1, Senior-Loken syndrome 1 (ClinVar).

How common is NPHP1 p.Pro186fs (c.555dup) in the general population?

NPHP1 p.Pro186fs (c.555dup) is very rare (popmax 0.00807%, nfe) (gnomAD).

NPHP1 p.Pro186fs

c.555dup · rs766524637 · VCV283524

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00807%, nfe)

Conditions

NPHP1-related disorder

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	27.1	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 0.00807% European (non-Finnish) · 95/1,177,812 alleles

Filtering AF 0.00674% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00626%

Overall 0.0067% 108/1,610,742 alleles · very rare exomes 101/1,459,376 · genomes 7/151,366 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00962%	10,394
European (non-Finnish)grpmax	0.00807%	12,398
African / African-American	0.00537%	18,639
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,562
South Asian	0.0022%	45,478

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro186fs
Coding: c.555dup
MANE Select: NM_001128178
dbSNP: rs766524637
Type: Duplication
Location: chr2:110168520 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB
Residue 186: the sh3 domain; a β-strand

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

Disease context

NPHP1-related disorder

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

Similar variants

NPHP1 p.Pro186= Likely benign ★★ same residue
NPHP1 p.Leu340fs Pathogenic/Likely pathogenic ★★ same condition
NPHP1 p.Thr461fs Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.144-11dup Benign/Likely benign ★★ same condition
NPHP1 c.1717-1dup Likely pathogenic ★ same condition
NPHP1 c.771+37_771+38dup Likely pathogenic ★ same condition
NPHP1 p.Arg204fs Pathogenic ★ same condition
NPHP1 p.Cys604fs 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-pro186fs (accessed [today's date]).

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