Is NPHP1 p.Asn146= (c.438T>C) pathogenic?

NPHP1 p.Asn146= (c.438T>C) is classified Benign/Likely benign in NPHP1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-24). Rare (popmax 0.685%, sas); Associated with Joubert syndrome with renal defect.

What condition is associated with NPHP1 p.Asn146= (c.438T>C)?

NPHP1 p.Asn146= (c.438T>C) is associated with Joubert syndrome with renal defect, nephronophthisis 1, Senior-Loken syndrome 1 (ClinVar).

How common is NPHP1 p.Asn146= (c.438T>C) in the general population?

NPHP1 p.Asn146= (c.438T>C) is rare (popmax 0.685%, sas) (gnomAD).

NPHP1 p.Asn146=

c.438T>C · rs548684868 · VCV462708

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.685%, sas)

Conditions

Joubert syndrome with renal defect

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 0.11	GERP -2.4
Overall
CADD	2.597	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.685% South Asian · 624/91,038 alleles

Filtering AF 0.641% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.623%

Overall 0.0402% 648/1,613,212 alleles · rare exomes 616/1,461,184 · genomes 32/152,028 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.685%	146
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.024%	4,165
European (non-Finnish)	0.000594%	168,486

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.Asn146=
Coding: c.438T>C
MANE Select: NM_001128178
dbSNP: rs548684868
Type: single nucleotide variant
Location: chr2:110169890 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB
Residue 146: the 'disordered' region

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

Disease context

Joubert syndrome with renal defect — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 1 Senior-Loken syndrome 1 nephronophthisis

Similar variants

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
NPHP1 c.522+1G>A 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-asn146 (accessed [today's date]).

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