Is NPHP3 p.Arg1118Cys (c.3352C>T) pathogenic?

NPHP3 p.Arg1118Cys (c.3352C>T) is classified Uncertain significance in NPHP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-30). AlphaMissense: ambiguous (0.4637); Very rare (popmax 0.004%, afr); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Arg1118Cys (c.3352C>T)?

NPHP3 p.Arg1118Cys (c.3352C>T) is associated with nephronophthisis (ClinVar).

How common is NPHP3 p.Arg1118Cys (c.3352C>T) in the general population?

NPHP3 p.Arg1118Cys (c.3352C>T) is very rare (popmax 0.004%, afr) (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.Arg1118Cys (c.3352C>T)?

AlphaMissense predicts ambiguous (score 0.4637) — an in-silico prediction, not a clinical call.

NPHP3 p.Arg1118Cys

c.3352C>T · rs757710406 · VCV1400848

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4637 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.4637	ambiguous
REVEL	0.807	moderately pathogenic-leaning
SaProt	LLR -10.53	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	33.0	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 0.004% African / African-American · 3/74,918 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000744% 12/1,613,480 alleles · very rare exomes 10/1,461,298 · genomes 2/152,182 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,973
East Asian	0.00223%	44,888
Admixed American	0.00167%	59,988
South Asian	0.0011%	91,086
European (non-Finnish)	0.000508%	196,657

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.Arg1118Cys
Coding: c.3352C>T
MANE Select: NM_153240
dbSNP: rs757710406
Type: single nucleotide variant
Location: chr3:132684772 (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.Arg1118His 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-arg1118cys (accessed [today's date]).

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