Is NPHP1 p.Tyr294Ter (c.882C>A) pathogenic?

NPHP1 p.Tyr294Ter (c.882C>A) is classified Pathogenic/Likely pathogenic in NPHP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-28). Very rare (popmax 0.000424%, nfe); Associated with NPHP1-related disorder.

What condition is associated with NPHP1 p.Tyr294Ter (c.882C>A)?

NPHP1 p.Tyr294Ter (c.882C>A) is associated with NPHP1-related disorder, Joubert syndrome with renal defect (ClinVar).

How common is NPHP1 p.Tyr294Ter (c.882C>A) in the general population?

NPHP1 p.Tyr294Ter (c.882C>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

NPHP1 p.Tyr294Ter

c.882C>A · rs369977541 · VCV2677262

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

NPHP1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 20
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.9	GERP 0.35, phastCons 1
Overall
CADD	37.0	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 0.000424% European (non-Finnish) · 5/1,178,734 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,612,428 alleles · very rare exomes 3/1,460,336 · genomes 2/152,092 · 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.Tyr294Ter
Coding: c.882C>A
MANE Select: NM_001128178
dbSNP: rs369977541
Type: single nucleotide variant
Location: chr2:110161675 (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

NPHP1-related disorder

Also linked: Joubert syndrome with renal defect

Similar variants

NPHP1 p.Tyr294= Likely benign ★ same residue
NPHP1 c.1083+1G>A Likely pathogenic ★★ same condition
NPHP1 c.1270-1G>A Pathogenic ★★ same condition
NPHP1 c.1270-2A>G Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.143+1G>C Likely pathogenic ★★ same condition
NPHP1 c.144-1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.1716+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.329+1G>A 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/nphp1-p-tyr294ter (accessed [today's date]).

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