Is NPHP3 p.Leu376Ter (c.1127T>A) pathogenic?

NPHP3 p.Leu376Ter (c.1127T>A) is classified Likely pathogenic in NPHP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-05). Very rare (popmax 0.000932%, nfe); Associated with NPHP3-related disorder.

What condition is associated with NPHP3 p.Leu376Ter (c.1127T>A)?

NPHP3 p.Leu376Ter (c.1127T>A) is associated with NPHP3-related disorder (ClinVar).

How common is NPHP3 p.Leu376Ter (c.1127T>A) in the general population?

NPHP3 p.Leu376Ter (c.1127T>A) is very rare (popmax 0.000932%, nfe) (gnomAD).

NPHP3 p.Leu376Ter

c.1127T>A · VCV4964297

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Conditions

NPHP3-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 27
Splicing
SpliceAI	Δ0.61	acceptor gain · deltas
Pangolin	Δ0.39	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.8	GERP -3.1, phastCons 0.64
Overall
CADD	36.0	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 0.000932% European (non-Finnish) · 11/1,180,010 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.00124% 20/1,613,942 alleles · very rare exomes 19/1,461,714 · genomes 1/152,228 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0109%	9,140
Remaining individualsnot grpmax-eligible	0.0032%	31,237
European (non-Finnish)grpmax	0.000932%	107,274

Finnish 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.Leu376Ter
Coding: c.1127T>A
MANE Select: NM_153240
Type: single nucleotide variant
Location: chr3:132708249 (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

NPHP3-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NPHP3 c.823+1G>T Likely pathogenic ★★ same condition
NPHP3 p.Arg142Ter Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Arg577Ter Pathogenic ★★ same condition
NPHP3 p.Arg702Ter Pathogenic ★★ same condition
NPHP3 p.Gln1136Ter Pathogenic ★★ same condition
NPHP3 p.Glu461Ter Pathogenic ★★ same condition
NPHP3 p.Gly935= Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Trp606Ter 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-leu376ter (accessed [today's date]).

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