Is NPHP4 p.Ala565fs (c.1692_1704del) pathogenic?

NPHP4 p.Ala565fs (c.16921704del) is classified Pathogenic/Likely pathogenic in NPHP4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-17). Very rare (popmax 0.000254%, nfe); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Ala565fs (c.1692_1704del)?

NPHP4 p.Ala565fs (c.1692_1704del) is associated with nephronophthisis, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Ala565fs (c.1692_1704del) in the general population?

NPHP4 p.Ala565fs (c.1692_1704del) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP4 p.Ala565fs

c.1692_1704del · rs1179512510 · VCV2872668

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

nephronophthisis

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 14 of 30
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,846 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,934 alleles · very rare exomes 3/1,461,568 · genomes 0/152,366 · 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.Ala565fs
Coding: c.1692_1704del
MANE Select: NM_015102
dbSNP: rs1179512510
Type: Deletion
Location: chr1:5905691 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44

Full NPHP4 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 4 Senior-Loken syndrome 4

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP4 p.Ala565= Likely benign ★ same residue
NPHP4 c.3817-12_3818del Likely pathogenic ★★ same condition
NPHP4 p.Ala279fs 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
NPHP4 p.Lys424fs Pathogenic/Likely pathogenic ★★ same condition
NPHP4 p.Phe63fs 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-ala565fs (accessed [today's date]).

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