Is NPHP4 p.Ser376fs (c.1124_1125insCC) pathogenic?

NPHP4 p.Ser376fs (c.11241125insCC) is classified Likely pathogenic in NPHP4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-05). Very rare (popmax 0.000254%, nfe); Associated with nephronophthisis 4.

What condition is associated with NPHP4 p.Ser376fs (c.1124_1125insCC)?

NPHP4 p.Ser376fs (c.1124_1125insCC) is associated with nephronophthisis 4 (ClinVar).

How common is NPHP4 p.Ser376fs (c.1124_1125insCC) in the general population?

NPHP4 p.Ser376fs (c.1124_1125insCC) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP4 p.Ser376fs

c.1124_1125insCC · rs1570504754 · VCV829827

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

nephronophthisis 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 10 of 30
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.7	GERP -3.8

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,588 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00031% 5/1,612,240 alleles · very rare exomes 5/1,459,898 · genomes 0/152,342 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,800
European (non-Finnish)grpmax	0.000254%	393,196

Ashkenazi Jewish 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.Ser376fs
Coding: c.1124_1125insCC
MANE Select: NM_015102
dbSNP: rs1570504754
Type: Insertion
Location: chr1:5933324 (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 4 — 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.Ser376Ala Uncertain significance ★★ ⚠ same residue
NPHP4 p.Ser376Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
NPHP4 p.Thr442fs Likely pathogenic ★ same condition
NPHP4 p.Ser376= Likely benign ★ same residue
NPHP4 p.Ala384fs Pathogenic 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-ser376fs (accessed [today's date]).

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