Is NPHP3 p.Phe1001fs (c.3003del) pathogenic?

NPHP3 p.Phe1001fs (c.3003del) is classified Pathogenic in NPHP3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-31). Very rare (popmax 0.00525%, nfe); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Phe1001fs (c.3003del)?

NPHP3 p.Phe1001fs (c.3003del) is associated with nephronophthisis, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Phe1001fs (c.3003del) in the general population?

NPHP3 p.Phe1001fs (c.3003del) is very rare (popmax 0.00525%, nfe) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP3 p.Phe1001fs

c.3003del · rs1560002113 · VCV853024

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00525%, 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 21 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.3	GERP 1.7, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00525% European (non-Finnish) · 62/1,179,998 alleles

Filtering AF 0.00418% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.0039% 63/1,614,086 alleles · very rare exomes 63/1,461,870 · genomes 0/152,216 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00525%	19,032
Remaining individualsnot grpmax-eligible	0.0016%	62,504

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.Phe1001fs
Coding: c.3003del
MANE Select: NM_153240
dbSNP: rs1560002113
Type: Deletion
Location: chr3:132688772 (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.Arg157fs Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Glu90_Tyr91insTer Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.His559fs Pathogenic/Likely 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-phe1001fs (accessed [today's date]).

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