Is NPHP1 p.Arg389Pro (c.1166G>C) pathogenic?

NPHP1 p.Arg389Pro (c.1166G>C) is classified Uncertain significance in NPHP1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-21). AlphaMissense: ambiguous (0.5053); No allele count reported in gnomAD v4.1 (AN 1,585,088); Associated with nephronophthisis.

What condition is associated with NPHP1 p.Arg389Pro (c.1166G>C)?

NPHP1 p.Arg389Pro (c.1166G>C) is associated with nephronophthisis (ClinVar).

How common is NPHP1 p.Arg389Pro (c.1166G>C) in the general population?

NPHP1 p.Arg389Pro (c.1166G>C) is no allele count reported in gnomAD v4.1 (AN 1,585,088) (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 NPHP1 p.Arg389Pro (c.1166G>C)?

AlphaMissense predicts ambiguous (score 0.5053) — an in-silico prediction, not a clinical call.

NPHP1 p.Arg389Pro

c.1166G>C · rs140979636 · VCV968146

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5053 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,585,088)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.5053	ambiguous
REVEL	0.166	moderately benign-leaning
SaProt	LLR -5.73	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	24.2	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 R444P vs ClinVar R389P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,585,088). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: NPHP1
Protein: p.Arg389Pro
Coding: c.1166G>C
MANE Select: NM_001128178
dbSNP: rs140979636
Type: single nucleotide variant
Location: chr2:110148019 (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

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

NPHP1 p.Arg389Cys Uncertain significance ★★ ⚠ same residue
NPHP1 p.Arg389His Uncertain significance ★★ ⚠ same residue
NPHP1 p.Arg389Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
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-arg389pro (accessed [today's date]).

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