Is NPHP4 c.1503+3A>C pathogenic?

NPHP4 c.1503+3A>C is classified Uncertain significance in NPHP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-19). Very rare (popmax 0.000256%, nfe); Associated with nephronophthisis.

What condition is associated with NPHP4 c.1503+3A>C?

NPHP4 c.1503+3A>C is associated with nephronophthisis (ClinVar).

How common is NPHP4 c.1503+3A>C in the general population?

NPHP4 c.1503+3A>C is very rare (popmax 0.000256%, nfe) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP4 c.1503+3A>C

rs1184570247 · VCV1011709

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000256%, nfe)

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
Splice region	donor +3	donor splice region (+3, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	Δ0.87	donor loss, 3 bp away · masked 0 · deltas
Pangolin	Δ0.76	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.9	GERP 0.74, phastCons 1
Non-coding constraint	Z 2.89	1 kb window · o/e 0.76 · regional · uncalibrated
Overall
CADD	18.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000256% European (non-Finnish) · 3/1,170,720 alleles

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

Overall 0.000188% 3/1,595,300 alleles · very rare exomes 3/1,443,082 · genomes 0/152,218 · joint denominator

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
Coding: c.1503+3A>C
MANE Select: NM_015102
dbSNP: rs1184570247
Type: single nucleotide variant
Location: chr1:5909149 (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 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
NPHP4 c.3644+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.3644+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.518-2A>G Likely pathogenic ★★ same condition
NPHP4 c.992+2T>C Likely pathogenic ★★ same condition
NPHP4 p.Arg1109Ter 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-c-1503-plus-3a-c (accessed [today's date]).

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