Is NPHP3 p.Arg1076Trp (c.3226C>T) pathogenic?

NPHP3 p.Arg1076Trp (c.3226C>T) is classified Conflicting classifications of pathogenicity in NPHP3 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-04). AlphaMissense: likely pathogenic (0.6912); Rare (popmax 0.258%, sas); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Arg1076Trp (c.3226C>T)?

NPHP3 p.Arg1076Trp (c.3226C>T) is associated with nephronophthisis (ClinVar).

How common is NPHP3 p.Arg1076Trp (c.3226C>T) in the general population?

NPHP3 p.Arg1076Trp (c.3226C>T) is rare (popmax 0.258%, sas) (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.Arg1076Trp (c.3226C>T)?

AlphaMissense predicts likely pathogenic (score 0.6912) — an in-silico prediction, not a clinical call.

NPHP3 p.Arg1076Trp

c.3226C>T · rs553665584 · VCV577594

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.6912 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.258%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.6912	likely pathogenic
REVEL	0.831	moderately pathogenic-leaning
SaProt	LLR -8.88	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.27	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 5.8	GERP 0.87, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	26.6	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 0.258% South Asian · 235/91,068 alleles

Filtering AF 0.231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.221%

Overall 0.0165% 267/1,613,990 alleles · rare exomes 249/1,461,752 · genomes 18/152,238 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.258%	388
Remaining individualsnot grpmax-eligible	0.0192%	5,208
Middle Eastern	0.0165%	6,062
East Asian	0.00223%	44,862
European (non-Finnish)	0.00153%	65,552

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.Arg1076Trp
Coding: c.3226C>T
MANE Select: NM_153240
dbSNP: rs553665584
Type: single nucleotide variant
Location: chr3:132686363 (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

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP3 p.Arg1076Pro Uncertain significance ★ ⚠ 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.958-2A>G Pathogenic ★★ same condition
NPHP3 p.Arg1125Ter Pathogenic ★★ same condition
NPHP3 p.Arg1259Ter Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Arg142Ter 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-arg1076trp (accessed [today's date]).

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