Is NPHP3 c.957+16A>C pathogenic?

NPHP3 c.957+16A>C is classified Likely benign in NPHP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-26). Rare (popmax 0.107%, eas); Associated with nephronophthisis.

What condition is associated with NPHP3 c.957+16A>C?

NPHP3 c.957+16A>C is associated with nephronophthisis (ClinVar).

How common is NPHP3 c.957+16A>C in the general population?

NPHP3 c.957+16A>C is rare (popmax 0.107%, eas) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP3 c.957+16A>C

rs368705884 · VCV1626232

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.107%, eas)

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +16	near-intronic (+16 nt from the splice site)
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.12	GERP -3, phastCons 0.13
Overall
CADD	12.47	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.107% East Asian · 48/44,718 alleles

Filtering AF 0.0832% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0746%

Overall 0.00567% 91/1,603,840 alleles · rare exomes 82/1,451,652 · genomes 9/152,188 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.107%	932
Remaining individualsnot grpmax-eligible	0.0628%	1,592
African / African-American	0.00268%	37,357
Admixed American	0.00167%	59,964
South Asian	0.0011%	90,684

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: NPHP3
Coding: c.957+16A>C
MANE Select: NM_153240
dbSNP: rs368705884
Type: single nucleotide variant
Location: chr3:132715069 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.59 · 1 PDB

Full NPHP3 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

NPHP3 c.1985+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP3 c.3201+1G>T Likely pathogenic ★★ same condition
NPHP3 c.393+1G>C Likely pathogenic ★★ same condition
NPHP3 c.958-2A>G Pathogenic ★★ same condition
NPHP3 p.Arg1125Ter Pathogenic ★★ same condition
NPHP3 p.Arg1259Ter Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Arg142Ter Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Arg577Ter 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/nphp3-c-957-plus-16a-c (accessed [today's date]).

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