Is NPHP3 p.Thr136fs (c.406del) pathogenic?

NPHP3 p.Thr136fs (c.406del) is classified Pathogenic/Likely pathogenic in NPHP3 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-15). Ultra-rare (popmax 0.0115%, nfe); Associated with NPHP3-related disorder.

What condition is associated with NPHP3 p.Thr136fs (c.406del)?

NPHP3 p.Thr136fs (c.406del) is associated with NPHP3-related disorder, nephronophthisis 3, nephronophthisis (ClinVar).

How common is NPHP3 p.Thr136fs (c.406del) in the general population?

NPHP3 p.Thr136fs (c.406del) is ultra-rare (popmax 0.0115%, nfe) (gnomAD).

NPHP3 p.Thr136fs

c.406del · rs1379989124 · VCV598394

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0115%, 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 2 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.9	GERP 1.5, phastCons 1
Overall
CADD	33.0	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 0.0115% European (non-Finnish) · 134/1,164,622 alleles

Filtering AF 0.0099% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0093%

Overall 0.00869% 138/1,588,106 alleles · ultra-rare exomes 135/1,436,624 · genomes 3/151,482 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0115%	8,691
South Asian	0.00229%	43,704
Admixed American	0.0017%	58,968
African / African-American	0.00134%	74,408

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.Thr136fs
Coding: c.406del
MANE Select: NM_153240
dbSNP: rs1379989124
Type: Deletion
Location: chr3:132719818 (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 3 nephronophthisis congenital anomaly of kidney and urinary tract

Similar variants

NPHP3 p.Thr136= Conflicting classifications of pathogenicity ★ same residue
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.Met491fs Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Phe1001fs Pathogenic ★★ same condition
NPHP3 p.Val363fs Pathogenic/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/nphp3-p-thr136fs (accessed [today's date]).

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