Is NPHP1 c.728+8del pathogenic?

NPHP1 c.728+8del is classified Likely benign in NPHP1 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-09-23). Ultra-rare (popmax 0.012%, afr); Associated with nephronophthisis.

What condition is associated with NPHP1 c.728+8del?

NPHP1 c.728+8del is associated with nephronophthisis (ClinVar).

How common is NPHP1 c.728+8del in the general population?

NPHP1 c.728+8del is ultra-rare (popmax 0.012%, afr) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP1 c.728+8del

rs863224357 · VCV215727

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +8	near-intronic (+8 nt from the splice site)
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -3.1	GERP 0.35
Non-coding constraint	Z 1.34	1 kb window · o/e 0.88 · regional · uncalibrated
Overall
CADD	8.216	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/74,700 alleles

Filtering AF 0.00625% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00469%

Overall 0.000561% 9/1,604,682 alleles · ultra-rare exomes 2/1,452,578 · genomes 7/152,104 · joint denominator

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.728+8del
MANE Select: NM_001128178
dbSNP: rs863224357
Type: Deletion
Location: chr2:110165044 (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 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-728-plus-8del (accessed [today's date]).

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