Is NPHP4 p.Lys83del (c.248_250del) pathogenic?

NPHP4 p.Lys83del (c.248250del) is classified Uncertain significance in NPHP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-21). Very rare (popmax 0.0011%, nfe); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Lys83del (c.248_250del)?

NPHP4 p.Lys83del (c.248_250del) is associated with nephronophthisis (ClinVar).

How common is NPHP4 p.Lys83del (c.248_250del) in the general population?

NPHP4 p.Lys83del (c.248_250del) is very rare (popmax 0.0011%, nfe) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP4 p.Lys83del

c.248_250del · rs1429611570 · VCV1935618

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.17	GERP 1.5

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,177,842 alleles

Filtering AF 0.000616% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000475%

Overall 0.00087% 14/1,608,668 alleles · very rare exomes 14/1,456,458 · genomes 0/152,210 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,308
European (non-Finnish)grpmax	0.0011%	90,604

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Lys83del
Coding: c.248_250del
MANE Select: NM_015102
dbSNP: rs1429611570
Type: Deletion
Location: chr1:5978299 (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

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP4 p.Lys83Asn Uncertain significance ★ ⚠ same residue
NPHP4 p.Lys83= Likely benign ★ 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-lys83del (accessed [today's date]).

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