Is NPHP4 p.Lys474fs (c.1421_1423delinsCGTGG) pathogenic?

NPHP4 p.Lys474fs (c.14211423delinsCGTGG) is classified Pathogenic/Likely pathogenic in NPHP4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-04). No gnomAD frequency available for this variant; Associated with Senior-Loken syndrome 4.

What condition is associated with NPHP4 p.Lys474fs (c.1421_1423delinsCGTGG)?

NPHP4 p.Lys474fs (c.1421_1423delinsCGTGG) is associated with Senior-Loken syndrome 4, nephronophthisis 4, nephronophthisis (ClinVar).

How common is NPHP4 p.Lys474fs (c.1421_1423delinsCGTGG) in the general population?

NPHP4 p.Lys474fs (c.1421_1423delinsCGTGG) is no gnomAD frequency available for this variant (gnomAD).

How is Senior-Loken syndrome inherited?

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

NPHP4 p.Lys474fs

c.1421_1423delinsCGTGG · rs1553178047 · VCV503803

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Senior-Loken syndrome 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 11 of 30
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.8	GERP -0.28, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: NPHP4
Protein: p.Lys474fs
Coding: c.1421_1423delinsCGTGG
MANE Select: NM_015102
dbSNP: rs1553178047
Type: Indel
Location: chr1:5927667 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 474: the 'disordered' region

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

Disease context

Senior-Loken syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 4 nephronophthisis

For Senior-Loken syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

NPHP4 p.Gln748Lys Uncertain significance ★★ same condition
NPHP4 p.Leu1164fs Likely pathogenic ★ same condition
NPHP4 p.Gly929Arg Uncertain significance ★ same condition
NPHP4 p.Met1075Trp Uncertain significance ★ same condition
NPHP4 p.Val291_Phe297delinsLeu Uncertain significance ★ same condition
NPHP4 c.2304+1G>A Pathogenic ★★ same condition
NPHP4 c.2611+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.2611+1G>C 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-lys474fs (accessed [today's date]).

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