Is NPHP1 p.Arg353Cys (c.1057C>T) pathogenic?

NPHP1 p.Arg353Cys (c.1057C>T) is classified Uncertain significance in NPHP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-03). AlphaMissense: ambiguous (0.3907); Ultra-rare (popmax 0.0143%, sas); Associated with nephronophthisis 1.

What condition is associated with NPHP1 p.Arg353Cys (c.1057C>T)?

NPHP1 p.Arg353Cys (c.1057C>T) is associated with nephronophthisis 1, Senior-Loken syndrome 1, Joubert syndrome with renal defect (ClinVar).

How common is NPHP1 p.Arg353Cys (c.1057C>T) in the general population?

NPHP1 p.Arg353Cys (c.1057C>T) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

What do computational predictors say about NPHP1 p.Arg353Cys (c.1057C>T)?

AlphaMissense predicts ambiguous (score 0.3907) — an in-silico prediction, not a clinical call.

NPHP1 p.Arg353Cys

c.1057C>T · VCV3584252

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3907 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Conditions

nephronophthisis 1

Computational evidence

Protein change
AlphaMissense	0.3907	ambiguous
REVEL	0.63	indeterminate
SaProt	LLR -12.77	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.50 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.7	GERP 0.75, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R408C vs ClinVar R353C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0143% South Asian · 13/91,048 alleles

Filtering AF 0.00845% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.00161% 26/1,612,614 alleles · ultra-rare exomes 25/1,460,604 · genomes 1/152,010 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	7,004
East Asian	0.00223%	44,782
Admixed American	0.00167%	59,970
European (non-Finnish)	0.000933%	107,180

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.Arg353Cys
Coding: c.1057C>T
MANE Select: NM_001128178
Type: single nucleotide variant
Location: chr2:110160153 (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

nephronophthisis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Senior-Loken syndrome 1 Joubert syndrome with renal defect

Similar variants

NPHP1 p.Arg353His Uncertain significance ★★ ⚠ same residue
NPHP1 p.Arg353= 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

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-arg353cys (accessed [today's date]).

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