Is NPHP1 c.69+1del pathogenic?

NPHP1 c.69+1del is classified Conflicting classifications of pathogenicity in NPHP1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-03-30). Ultra-rare (popmax 0.0166%, mid); Associated with nephronophthisis.

What condition is associated with NPHP1 c.69+1del?

NPHP1 c.69+1del is associated with nephronophthisis, nephronophthisis 1, Senior-Loken syndrome 1 (ClinVar).

How common is NPHP1 c.69+1del in the general population?

NPHP1 c.69+1del is ultra-rare (popmax 0.0166%, mid) (gnomAD).

How is Nephronophthisis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

NPHP1 c.69+1del

rs1435671751 · VCV2677270

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +1	canonical splice dinucleotide (donor +1) · inside the BP7-excluded zone
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.6	GERP 0.48, phastCons 1
Non-coding constraint	Z -0.45	1 kb window · o/e 1.03 · regional · uncalibrated
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,016 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,610 alleles · ultra-rare exomes 2/1,461,498 · genomes 1/152,112 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,016
European (non-Finnish)	0.00017%	589,918

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
Coding: c.69+1del
MANE Select: NM_001128178
dbSNP: rs1435671751
Type: Deletion
Location: chr2:110204899 (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

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

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP1 c.141_143+40del Likely pathogenic ★★ same condition
NPHP1 p.Asn61fs Pathogenic/Likely pathogenic ★★ same condition
NPHP1 p.Asp162fs Pathogenic/Likely pathogenic ★★ same condition
NPHP1 p.Glu454fs Pathogenic ★★ same condition
NPHP1 p.Ile517fs Pathogenic ★★ same condition
NPHP1 p.Lys185fs Pathogenic ★★ same condition
NPHP1 p.Lys377fs Pathogenic ★★ same condition
NPHP1 p.Ser129fs 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-c-69-plus-1del (accessed [today's date]).

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