Is NPHP1 p.Val202Leu (c.604G>C) pathogenic?

NPHP1 p.Val202Leu (c.604G>C) is classified Uncertain significance in NPHP1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-02-06). AlphaMissense: ambiguous (0.5023); Ultra-rare (popmax 0.0167%, amr); Associated with nephronophthisis 1.

What condition is associated with NPHP1 p.Val202Leu (c.604G>C)?

NPHP1 p.Val202Leu (c.604G>C) is associated with nephronophthisis 1, Senior-Loken syndrome 1, Joubert syndrome with renal defect (ClinVar).

How common is NPHP1 p.Val202Leu (c.604G>C) in the general population?

NPHP1 p.Val202Leu (c.604G>C) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about NPHP1 p.Val202Leu (c.604G>C)?

AlphaMissense predicts ambiguous (score 0.5023) — an in-silico prediction, not a clinical call.

NPHP1 p.Val202Leu

c.604G>C · rs753605280 · VCV959022

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5023 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

nephronophthisis 1

Computational evidence

Protein change
AlphaMissense	0.5023	ambiguous
REVEL	0.149	moderately benign-leaning
SaProt	LLR -12.00	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -1.9
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	13.15	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 0.0167% Admixed American · 10/59,958 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00682%

Overall 0.000682% 11/1,611,762 alleles · ultra-rare exomes 10/1,459,994 · genomes 1/151,768 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,996
South Asian	0.0011%	91,016

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: NPHP1
Protein: p.Val202Leu
Coding: c.604G>C
MANE Select: NM_001128178
dbSNP: rs753605280
Type: single nucleotide variant
Location: chr2:110168472 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB
Residue 202: the sh3 domain; a β-strand

Full NPHP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephronophthisis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Senior-Loken syndrome 1 Joubert syndrome with renal defect nephronophthisis

Similar variants

NPHP1 p.Val202Phe Uncertain significance ★★ ⚠ same residue
NPHP1 p.Val202= Likely benign ★ same residue
NPHP1 c.1083+1G>A Likely pathogenic ★★ same condition
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-val202leu (accessed [today's date]).

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