Is NPHP3 p.Gln1326fs (c.3975del) pathogenic?

NPHP3 p.Gln1326fs (c.3975del) is classified Uncertain significance in NPHP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-10). Very rare (popmax 0.000509%, nfe); Associated with NPHP3-related Meckel-like syndrome.

What condition is associated with NPHP3 p.Gln1326fs (c.3975del)?

NPHP3 p.Gln1326fs (c.3975del) is associated with NPHP3-related Meckel-like syndrome, renal-hepatic-pancreatic dysplasia 1, nephronophthisis 3 (ClinVar).

How common is NPHP3 p.Gln1326fs (c.3975del) in the general population?

NPHP3 p.Gln1326fs (c.3975del) is very rare (popmax 0.000509%, nfe) (gnomAD).

NPHP3 p.Gln1326fs

c.3975del · VCV3588510

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Conditions

NPHP3-related Meckel-like syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (27 of 27) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 8.5	GERP 0.07, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000509% European (non-Finnish) · 6/1,179,866 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,988 alleles · very rare exomes 6/1,461,680 · genomes 0/152,308 · 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.Gln1326fs
Coding: c.3975del
MANE Select: NM_153240
Type: Deletion
Location: chr3:132681928 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.59 · 1 PDB
Residue 1326: the 'disordered' region

Full NPHP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: renal-hepatic-pancreatic dysplasia 1 nephronophthisis 3

Similar variants

NPHP3 c.3570+1del Likely pathogenic ★★ same condition
NPHP3 p.Arg157fs 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.1887+17del Likely benign ★★ same condition
NPHP3 c.2571_2574del 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-gln1326fs (accessed [today's date]).

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