Is NPHP3 p.Arg1305Cys (c.3913C>T) pathogenic?

NPHP3 p.Arg1305Cys (c.3913C>T) is classified Benign/Likely benign in NPHP3 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0861); Common (popmax 5.74%, afr) — too common for a highly-penetrant pathogenic allele; Associated with kidney disorder.

What condition is associated with NPHP3 p.Arg1305Cys (c.3913C>T)?

NPHP3 p.Arg1305Cys (c.3913C>T) is associated with kidney disorder, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

What do computational predictors say about NPHP3 p.Arg1305Cys (c.3913C>T)?

AlphaMissense predicts likely benign (score 0.0861) — an in-silico prediction, not a clinical call.

NPHP3 p.Arg1305Cys

Q: How common is NPHP3 p.Arg1305Cys (c.3913C>T) in the general population?

NPHP3 p.Arg1305Cys (c.3913C>T) is common (popmax 5.74%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3913C>T · rs35485382 · VCV218850

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0861 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.74%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

kidney disorder

Computational evidence

Protein change
AlphaMissense	0.0861	likely benign
REVEL	0.234	benign-leaning
SaProt	LLR -7.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.6	GERP -2, phastCons 0.14
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	20.4	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 5.74% African / African-American · 4,304/75,028 alleles

Filtering AF 5.59% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.54%

Overall 0.296% 4,770/1,613,880 alleles · common exomes 2,397/1,461,600 · genomes 2,373/152,280 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.74%	17
Remaining individualsnot grpmax-eligible	0.376%	266
Admixed American	0.268%	373
Middle Eastern	0.198%	505
East Asian	0.0223%	4,486
South Asian	0.00659%	15,181
European (non-Finnish)	0.00348%	28,775
Finnishnot grpmax-eligible	0.00156%	64,036

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.Arg1305Cys
Coding: c.3913C>T
MANE Select: NM_153240
dbSNP: rs35485382
Type: single nucleotide variant
Location: chr3:132681990 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.59 · 1 PDB
Residue 1305: the 'disordered' region; a UniProt-annotated variant site (in)

Full NPHP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

kidney disorder — 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 nephronophthisis

Similar variants

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
NPHP3 p.Arg1259Ter 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/nphp3-p-arg1305cys (accessed [today's date]).

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