Is NPHP4 p.Val582del (c.1740TGT[1]) pathogenic?

NPHP4 p.Val582del (c.1740TGT[1]) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-21). Ultra-rare (popmax 0.0329%, mid); Associated with Senior-Loken syndrome 4.

What condition is associated with NPHP4 p.Val582del (c.1740TGT[1])?

NPHP4 p.Val582del (c.1740TGT[1]) is associated with Senior-Loken syndrome 4, nephronophthisis 4, nephronophthisis (ClinVar).

How common is NPHP4 p.Val582del (c.1740TGT[1]) in the general population?

NPHP4 p.Val582del (c.1740TGT[1]) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

How is Senior-Loken syndrome inherited?

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

NPHP4 p.Val582del

c.1740TGT[1] · rs1282891020 · VCV501861

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

Senior-Loken syndrome 4

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 0.41	GERP -4.3, phastCons 0.12
Overall
CADD	0.903	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00062% 10/1,613,802 alleles · ultra-rare exomes 9/1,461,604 · genomes 1/152,198 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
African / African-American	0.00267%	37,452
Remaining individualsnot grpmax-eligible	0.0016%	62,466
European (non-Finnish)	0.000424%	235,974

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.Val582del
Coding: c.1740TGT[1]
MANE Select: NM_015102
dbSNP: rs1282891020
Type: Microsatellite
Location: chr1:5905650 (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

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.Val1123fs Pathogenic/Likely pathogenic ★★ same condition
NPHP4 p.Arg20fs Pathogenic ★ same condition
NPHP4 p.Arg22fs Likely pathogenic ★ same condition
NPHP4 p.Gln1002fs Likely pathogenic ★ same condition
NPHP4 p.His1267fs Pathogenic ★ same condition
NPHP4 p.Phe62fs Likely pathogenic ★ same condition
NPHP4 p.Tyr667fs Pathogenic ★ same condition
NPHP4 c.1764-7_1764-6del Likely benign ★ 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-val582del (accessed [today's date]).

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