Is NPHP1 p.Ile45Leu (c.133A>C) pathogenic?

NPHP1 p.Ile45Leu (c.133A>C) is classified Benign/Likely benign in NPHP1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.1136); Rare (popmax 0.623%, afr); Associated with kidney disorder.

What condition is associated with NPHP1 p.Ile45Leu (c.133A>C)?

NPHP1 p.Ile45Leu (c.133A>C) is associated with kidney disorder, nephronophthisis (ClinVar).

How common is NPHP1 p.Ile45Leu (c.133A>C) in the general population?

NPHP1 p.Ile45Leu (c.133A>C) is rare (popmax 0.623%, afr) (gnomAD).

What do computational predictors say about NPHP1 p.Ile45Leu (c.133A>C)?

AlphaMissense predicts likely benign (score 0.1136) — an in-silico prediction, not a clinical call.

NPHP1 p.Ile45Leu

c.133A>C · rs145479679 · VCV92717

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1136 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.623%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

kidney disorder

Computational evidence

Protein change
AlphaMissense	0.1136	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -4.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.56	GERP 0.47, phastCons 0.53
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	12.97	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 0.623% African / African-American · 467/74,922 alleles

Filtering AF 0.577% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.558%

Overall 0.0311% 499/1,605,010 alleles · rare exomes 214/1,452,720 · genomes 285/152,290 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.623%	160
Admixed American	0.0267%	3,742
Remaining individualsnot grpmax-eligible	0.0209%	4,784
European (non-Finnish)	0.000256%	391,083

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.Ile45Leu
Coding: c.133A>C
MANE Select: NM_001128178
dbSNP: rs145479679
Type: single nucleotide variant
Location: chr2:110201431 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB
Residue 45: an α-helix

Full NPHP1 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: nephronophthisis

Similar variants

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
NPHP1 c.329+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.522+1G>A Likely pathogenic ★★ same condition
NPHP1 c.729-2A>G 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-ile45leu (accessed [today's date]).

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