Is NPHP1 p.Arg353His (c.1058G>A) pathogenic?

NPHP1 p.Arg353His (c.1058G>A) is classified Uncertain significance in NPHP1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-05). AlphaMissense: likely benign (0.2657); Very rare (popmax 0.00644%, nfe); Associated with Senior-Loken syndrome 1.

What condition is associated with NPHP1 p.Arg353His (c.1058G>A)?

NPHP1 p.Arg353His (c.1058G>A) is associated with Senior-Loken syndrome 1, nephronophthisis 1, Joubert syndrome with renal defect (ClinVar).

How common is NPHP1 p.Arg353His (c.1058G>A) in the general population?

NPHP1 p.Arg353His (c.1058G>A) is very rare (popmax 0.00644%, nfe) (gnomAD).

How is Senior-Loken syndrome inherited?

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

What do computational predictors say about NPHP1 p.Arg353His (c.1058G>A)?

AlphaMissense predicts likely benign (score 0.2657) — an in-silico prediction, not a clinical call.

NPHP1 p.Arg353His

c.1058G>A · rs766289967 · VCV593284

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2657 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00644%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Senior-Loken syndrome 1

Computational evidence

Protein change
AlphaMissense	0.2657	likely benign
REVEL	0.595	indeterminate
SaProt	LLR -11.09	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	25.2	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 R408H vs ClinVar R353H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00644% European (non-Finnish) · 76/1,179,266 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00614% 99/1,612,944 alleles · very rare exomes 88/1,460,918 · genomes 11/152,026 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0203%	4,922
European (non-Finnish)grpmax	0.00644%	15,517
Admixed American	0.005%	19,992
East Asian	0.00447%	22,392
Remaining individualsnot grpmax-eligible	0.0032%	31,226
South Asian	0.0022%	45,530
African / African-American	0.00134%	74,842

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: NPHP1
Protein: p.Arg353His
Coding: c.1058G>A
MANE Select: NM_001128178
dbSNP: rs766289967
Type: single nucleotide variant
Location: chr2:110160152 (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.Arg353Cys 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-arg353his (accessed [today's date]).

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