Is NPHP4 p.Arg896fs (c.2686del) pathogenic?

NPHP4 p.Arg896fs (c.2686del) is classified Likely pathogenic in NPHP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-25). Very rare (popmax 0.00998%, sas); Associated with nephronophthisis 4.

What condition is associated with NPHP4 p.Arg896fs (c.2686del)?

NPHP4 p.Arg896fs (c.2686del) is associated with nephronophthisis 4 (ClinVar).

How common is NPHP4 p.Arg896fs (c.2686del) in the general population?

NPHP4 p.Arg896fs (c.2686del) is very rare (popmax 0.00998%, sas) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP4 p.Arg896fs

c.2686del · rs761183927 · VCV2506482

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00998%, sas)

Conditions

nephronophthisis 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 20 of 30
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.5	GERP -2.9

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00998% South Asian · 9/90,148 alleles

Filtering AF 0.00518% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00389%

Overall 0.00056% 9/1,608,024 alleles · very rare exomes 9/1,455,652 · genomes 0/152,372 · 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: NPHP4
Protein: p.Arg896fs
Coding: c.2686del
MANE Select: NM_015102
dbSNP: rs761183927
Type: Deletion
Location: chr1:5877224 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 896: the 'sufficient for basal bodies localization' region; the 'disordered' region

Full NPHP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephronophthisis 4 — 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

NPHP4 p.Arg896Trp Uncertain significance ★★ ⚠ same residue
NPHP4 p.Arg896Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
NPHP4 c.3817-12_3818del Likely pathogenic ★★ same condition
NPHP4 p.Ala279fs Pathogenic/Likely pathogenic ★★ same condition
NPHP4 p.Ala565fs Pathogenic/Likely pathogenic ★★ same condition
NPHP4 p.Gln1050fs Pathogenic/Likely pathogenic ★★ same condition
NPHP4 p.Gly1028fs Pathogenic/Likely pathogenic ★★ same condition
NPHP4 p.Gly529fs 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/nphp4-p-arg896fs (accessed [today's date]).

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