Is NPHP1 p.Leu340fs (c.1016dup) pathogenic?

NPHP1 p.Leu340fs (c.1016dup) is classified Pathogenic/Likely pathogenic in NPHP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-12-28). Very rare (popmax 8.48e-05%, nfe); Associated with nephronophthisis.

What condition is associated with NPHP1 p.Leu340fs (c.1016dup)?

NPHP1 p.Leu340fs (c.1016dup) is associated with nephronophthisis, Joubert syndrome with renal defect (ClinVar).

How common is NPHP1 p.Leu340fs (c.1016dup) in the general population?

NPHP1 p.Leu340fs (c.1016dup) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP1 p.Leu340fs

c.1016dup · rs398123285 · VCV92716

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, 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 11 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.1	GERP -2.8, phastCons 0.99

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,178,614 alleles

Overall 6.2e-05% 1/1,612,500 alleles · very rare exomes 1/1,460,214 · genomes 0/152,286 · 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: NPHP1
Protein: p.Leu340fs
Coding: c.1016dup
MANE Select: NM_001128178
dbSNP: rs398123285
Type: Duplication
Location: chr2:110160193 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB

Full NPHP1 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: Joubert syndrome with renal defect

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP1 p.Leu340Phe Uncertain significance ★ ⚠ same residue
NPHP1 p.Pro186fs 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.Cys604fs Pathogenic ★ same condition
NPHP1 p.Gln282fs 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-leu340fs (accessed [today's date]).

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