Is NPHP3 p.Leu1253= (c.3759G>A) pathogenic?

NPHP3 p.Leu1253= (c.3759G>A) is classified Benign/Likely benign in NPHP3 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 58.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with nephronophthisis.

What condition is associated with NPHP3 p.Leu1253= (c.3759G>A)?

NPHP3 p.Leu1253= (c.3759G>A) is associated with nephronophthisis, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How is Nephronophthisis inherited?

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

NPHP3 p.Leu1253=

Q: How common is NPHP3 p.Leu1253= (c.3759G>A) in the general population?

NPHP3 p.Leu1253= (c.3759G>A) is common (popmax 58.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3759G>A · rs6794496 · VCV262710

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 58.9%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.1, phastCons 1
Overall
CADD	9.279	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 58.9% East Asian · 26,384/44,828 alleles

Filtering AF 58.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 58%

Overall 14.3% 231,080/1,612,284 alleles · common exomes 209,319/1,460,158 · genomes 21,761/152,126 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	58.9%	2
South Asian	16.9%	6
Finnishnot grpmax-eligible	16.7%	6
Remaining individualsnot grpmax-eligible	14.9%	7
European (non-Finnish)	12.9%	8
Amishnot grpmax-eligible	11.8%	9
African / African-American	11.1%	9
Middle Eastern	10.4%	10
Admixed American	8.68%	12
Ashkenazi Jewishnot grpmax-eligible	8.59%	12

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
Protein: p.Leu1253=
Coding: c.3759G>A
MANE Select: NM_153240
dbSNP: rs6794496
Type: single nucleotide variant
Location: chr3:132682756 (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

Also linked: renal-hepatic-pancreatic dysplasia 1 NPHP3-related Meckel-like syndrome nephronophthisis 3

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

NPHP3 p.Leu1253Val Likely pathogenic ★★ ⚠ same residue
NPHP3 p.Leu1253Met Uncertain significance ★ ⚠ same residue
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.520-1G>T Pathogenic ★★ same condition
NPHP3 c.823+1G>T Likely pathogenic ★★ same condition
NPHP3 c.958-2A>G 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-p-leu1253 (accessed [today's date]).

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