Is NPHP4 p.Val1091fs (c.3272del) pathogenic?

NPHP4 p.Val1091fs (c.3272del) is classified Pathogenic in NPHP4 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-10-02). Very rare (popmax 0.00549%, sas); Associated with NPHP4-related disorder.

What condition is associated with NPHP4 p.Val1091fs (c.3272del)?

NPHP4 p.Val1091fs (c.3272del) is associated with NPHP4-related disorder, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Val1091fs (c.3272del) in the general population?

NPHP4 p.Val1091fs (c.3272del) is very rare (popmax 0.00549%, sas) (gnomAD).

NPHP4 p.Val1091fs

c.3272del · rs1278089386 · VCV3403

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Conditions

NPHP4-related disorder

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 23 of 30
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -7.8	GERP -3.4
Overall
CADD	18.41	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00549% South Asian · 5/91,082 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00186% 30/1,613,986 alleles · very rare exomes 26/1,461,666 · genomes 4/152,320 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,216
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)	0.00178%	56,184
African / African-American	0.00133%	75,056

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.Val1091fs
Coding: c.3272del
MANE Select: NM_015102
dbSNP: rs1278089386
Type: Deletion
Location: chr1:5873295 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1091: the 'sufficient for basal bodies localization' region

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

Disease context

Also linked: nephronophthisis 4 Senior-Loken syndrome 4 nephronophthisis

Similar variants

NPHP4 p.Val1091Met Uncertain significance ★★ ⚠ 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.Glu978fs 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-val1091fs (accessed [today's date]).

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