Is NPHP1 p.Pro186= (c.558T>G) pathogenic?

NPHP1 p.Pro186= (c.558T>G) is classified Likely benign in NPHP1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-06-01). Ultra-rare (popmax 0.0158%, nfe); Associated with nephronophthisis 1.

What condition is associated with NPHP1 p.Pro186= (c.558T>G)?

NPHP1 p.Pro186= (c.558T>G) is associated with nephronophthisis 1, Senior-Loken syndrome 1, Joubert syndrome with renal defect (ClinVar).

How common is NPHP1 p.Pro186= (c.558T>G) in the general population?

NPHP1 p.Pro186= (c.558T>G) is ultra-rare (popmax 0.0158%, nfe) (gnomAD).

NPHP1 p.Pro186=

c.558T>G · rs372637635 · VCV1136933

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0158%, nfe)

Conditions

nephronophthisis 1

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 -0.56	GERP -2.7
Overall
CADD	7.875	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0158% European (non-Finnish) · 186/1,179,336 alleles

Filtering AF 0.0138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0132%

Overall 0.0123% 198/1,613,176 alleles · ultra-rare exomes 191/1,461,068 · genomes 7/152,108 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0158%	6,341
Remaining individualsnot grpmax-eligible	0.0112%	8,921
African / African-American	0.00401%	24,963
Admixed American	0.00167%	59,988
South Asian	0.0011%	91,056

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.Pro186=
Coding: c.558T>G
MANE Select: NM_001128178
dbSNP: rs372637635
Type: single nucleotide variant
Location: chr2:110168518 (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

nephronophthisis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

NPHP1 p.Pro186fs Pathogenic ★★ same residue
NPHP1 c.1083+1G>A Likely pathogenic ★★ same condition
NPHP1 c.1270-1G>A Pathogenic ★★ same condition
NPHP1 c.1270-2A>G Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.143+1G>C Likely pathogenic ★★ same condition
NPHP1 c.144-1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.1716+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.329+1G>A 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-pro186 (accessed [today's date]).

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