Is NPHP3 p.Ser361Cys (c.1082C>G) pathogenic?

NPHP3 p.Ser361Cys (c.1082C>G) is classified Conflicting classifications of pathogenicity in NPHP3 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.2404); Rare (popmax 0.197%, eas); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Ser361Cys (c.1082C>G)?

NPHP3 p.Ser361Cys (c.1082C>G) is associated with nephronophthisis, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Ser361Cys (c.1082C>G) in the general population?

NPHP3 p.Ser361Cys (c.1082C>G) is rare (popmax 0.197%, eas) (gnomAD).

How is Nephronophthisis inherited?

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

What do computational predictors say about NPHP3 p.Ser361Cys (c.1082C>G)?

AlphaMissense predicts likely benign (score 0.2404) — an in-silico prediction, not a clinical call.

NPHP3 p.Ser361Cys

c.1082C>G · rs146250226 · VCV450392

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2404 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.197%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.2404	likely benign
REVEL	0.623	indeterminate
SaProt	LLR -0.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.197% East Asian · 86/43,632 alleles

Filtering AF 0.163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.151%

Overall 0.00619% 93/1,501,520 alleles · rare exomes 75/1,349,478 · genomes 18/152,042 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.197%	507
Remaining individualsnot grpmax-eligible	0.00686%	14,574
South Asian	0.00359%	27,828

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.Ser361Cys
Coding: c.1082C>G
MANE Select: NM_153240
dbSNP: rs146250226
Type: single nucleotide variant
Location: chr3:132713162 (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

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

Also linked: renal-hepatic-pancreatic dysplasia 1 NPHP3-related Meckel-like syndrome nephronophthisis 3

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

NPHP3 p.Ser361= Conflicting classifications of pathogenicity ★ same residue
NPHP3 c.1985+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP3 c.3201+1G>T Likely pathogenic ★★ same condition
NPHP3 c.393+1G>C Likely pathogenic ★★ same condition
NPHP3 c.520-1G>T Pathogenic ★★ same condition
NPHP3 c.823+1G>T Likely pathogenic ★★ same condition
NPHP3 c.958-2A>G Pathogenic ★★ same condition
NPHP3 p.Arg1125Ter 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-ser361cys (accessed [today's date]).

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