Is NPHP3 p.Ser1053fs (c.3156dup) pathogenic?

NPHP3 p.Ser1053fs (c.3156dup) is classified Pathogenic/Likely pathogenic in NPHP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-01). Very rare (popmax 0.00249%, nfe); Associated with NPHP3-related disorder.

What condition is associated with NPHP3 p.Ser1053fs (c.3156dup)?

NPHP3 p.Ser1053fs (c.3156dup) is associated with NPHP3-related disorder, nephronophthisis (ClinVar).

How common is NPHP3 p.Ser1053fs (c.3156dup) in the general population?

NPHP3 p.Ser1053fs (c.3156dup) is very rare (popmax 0.00249%, nfe) (gnomAD).

NPHP3 p.Ser1053fs

c.3156dup · rs771215577 · VCV411105

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00249%, nfe)

Conditions

NPHP3-related disorder

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 22 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.2	GERP 1.9, phastCons 1
Overall
CADD	34.0	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 0.00249% European (non-Finnish) · 26/1,042,572 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00147%

Overall 0.00192% 28/1,458,686 alleles · very rare exomes 27/1,306,702 · genomes 1/151,984 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00349%	28,641
European (non-Finnish)grpmax	0.00249%	40,099

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser1053fs
Coding: c.3156dup
MANE Select: NM_153240
dbSNP: rs771215577
Type: Duplication
Location: chr3:132687195 (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

Also linked: nephronophthisis

Similar variants

NPHP3 p.Ala158fs Likely pathogenic ★★ same condition
NPHP3 p.Gln986fs Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Ser1271Ter Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Gln1150dup Uncertain significance ★★ same condition
NPHP3 p.Met1fs Uncertain significance ★★ same condition
NPHP3 c.1525-13dup Benign/Likely benign ★★ same condition
NPHP3 c.3125+7dup Benign/Likely benign ★★ same condition
NPHP3 c.3571-10dup 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-ser1053fs (accessed [today's date]).

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