Is NPHP1 p.Arg291Ter (c.871C>T) pathogenic?

NPHP1 p.Arg291Ter (c.871C>T) is classified Pathogenic in NPHP1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-29). Very rare (popmax 0.005%, amr); Associated with Senior-Loken syndrome 1.

What condition is associated with NPHP1 p.Arg291Ter (c.871C>T)?

NPHP1 p.Arg291Ter (c.871C>T) is associated with Senior-Loken syndrome 1, nephronophthisis 1, Joubert syndrome with renal defect (ClinVar).

How common is NPHP1 p.Arg291Ter (c.871C>T) in the general population?

NPHP1 p.Arg291Ter (c.871C>T) is very rare (popmax 0.005%, amr) (gnomAD).

How is Senior-Loken syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

NPHP1 p.Arg291Ter

c.871C>T · rs765263671 · VCV579607

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

Senior-Loken syndrome 1

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 10 of 20
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Pangolin	Δ0.34	loss · gain 0.14 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Overall
CADD	47.0	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 0.005% Admixed American · 3/59,990 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000435% 7/1,610,268 alleles · very rare exomes 7/1,458,132 · genomes 0/152,136 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,997
East Asian	0.00223%	44,796
Finnishnot grpmax-eligible	0.00156%	63,924
South Asian	0.0011%	90,986
European (non-Finnish)	8.5e-05%	1,176,711

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.Arg291Ter
Coding: c.871C>T
MANE Select: NM_001128178
dbSNP: rs765263671
Type: single nucleotide variant
Location: chr2:110161686 (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

Senior-Loken syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 1 Joubert syndrome with renal defect nephronophthisis

For Senior-Loken syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

NPHP1 p.Arg291Gln Uncertain significance ★★ ⚠ 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-arg291ter (accessed [today's date]).

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