Is NPHP4 p.Ser1092fs (c.3272dup) pathogenic?

NPHP4 p.Ser1092fs (c.3272dup) is classified Pathogenic in NPHP4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-09). Ultra-rare (popmax 0.0176%, sas); Associated with Cystic renal disease.

What condition is associated with NPHP4 p.Ser1092fs (c.3272dup)?

NPHP4 p.Ser1092fs (c.3272dup) is associated with Cystic renal disease, nephronophthisis (ClinVar).

How common is NPHP4 p.Ser1092fs (c.3272dup) in the general population?

NPHP4 p.Ser1092fs (c.3272dup) is ultra-rare (popmax 0.0176%, sas) (gnomAD).

NPHP4 p.Ser1092fs

c.3272dup · rs777884325 · VCV2202693

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, sas)

Conditions

Cystic renal disease

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	18.71	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 0.0176% South Asian · 16/91,086 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00888%

Overall 0.00105% 17/1,613,868 alleles · ultra-rare exomes 16/1,461,666 · genomes 1/152,202 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0176%	5,693
Remaining individualsnot grpmax-eligible	0.0016%	62,460

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.Ser1092fs
Coding: c.3272dup
MANE Select: NM_015102
dbSNP: rs777884325
Type: Duplication
Location: chr1:5873294 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1092: the 'sufficient for basal bodies localization' region

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

Disease context

Cystic renal disease

Also linked: nephronophthisis

Similar variants

NPHP4 p.Ser1092Pro Uncertain significance ★ ⚠ same residue
NPHP4 p.His982fs Pathogenic ★★ same condition
NPHP4 p.Leu970fs Pathogenic/Likely pathogenic ★★ same condition
NPHP4 p.Ser251fs Pathogenic ★★ same condition
NPHP4 p.Thr1004fs Pathogenic ★★ same condition
NPHP4 c.1306_1314dup Uncertain significance ★★ same condition
NPHP4 c.3231+7dup Likely benign ★★ same condition
NPHP4 p.Ala1029fs 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-ser1092fs (accessed [today's date]).

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