Is NPHP3 p.Arg157fs (c.469del) pathogenic?

NPHP3 p.Arg157fs (c.469del) is classified Pathogenic/Likely pathogenic in NPHP3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-05-13). Very rare (popmax 0.000428%, nfe); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Arg157fs (c.469del)?

NPHP3 p.Arg157fs (c.469del) is associated with nephronophthisis, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Arg157fs (c.469del) in the general population?

NPHP3 p.Arg157fs (c.469del) is very rare (popmax 0.000428%, nfe) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP3 p.Arg157fs

c.469del · rs773760404 · VCV1454636

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000428%, 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 2 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Overall
CADD	29.2	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 0.000428% European (non-Finnish) · 5/1,167,644 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000314% 5/1,593,270 alleles · very rare exomes 2/1,441,328 · genomes 3/151,942 · 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: NPHP3
Protein: p.Arg157fs
Coding: c.469del
MANE Select: NM_153240
dbSNP: rs773760404
Type: Deletion
Location: chr3:132719755 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.59 · 1 PDB

Full NPHP3 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: renal-hepatic-pancreatic dysplasia 1 NPHP3-related Meckel-like syndrome nephronophthisis 3

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP3 c.3570+1del Likely pathogenic ★★ same condition
NPHP3 p.Glu90_Tyr91insTer Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.His559fs Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Phe1001fs Pathogenic ★★ same condition
NPHP3 p.Thr136fs Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Val363fs Pathogenic/Likely pathogenic ★★ same condition
NPHP3 c.3697-11_3697-7del Uncertain significance ★★ same condition
NPHP3 c.1118+17del Likely benign ★★ 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/nphp3-p-arg157fs (accessed [today's date]).

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