Is NPHP3 p.Leu110del (c.326TGT[1]) pathogenic?

NPHP3 p.Leu110del (c.326TGT[1]) is classified Conflicting classifications of pathogenicity in NPHP3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-06-21). Very rare (popmax 0.00446%, eas); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Leu110del (c.326TGT[1])?

NPHP3 p.Leu110del (c.326TGT[1]) is associated with nephronophthisis, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Leu110del (c.326TGT[1]) in the general population?

NPHP3 p.Leu110del (c.326TGT[1]) is very rare (popmax 0.00446%, eas) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP3 p.Leu110del

c.326TGT[1] · rs753616848 · VCV568513

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 0.57, phastCons 1
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,886 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000434% 7/1,613,106 alleles · very rare exomes 5/1,460,930 · genomes 2/152,176 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,443
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
Admixed American	0.00167%	60,010
European (non-Finnish)	0.000254%	393,301

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.Leu110del
Coding: c.326TGT[1]
MANE Select: NM_153240
dbSNP: rs753616848
Type: Microsatellite
Location: chr3:132722025 (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.Leu110Ser Uncertain significance ★ ⚠ same residue
NPHP3 p.Leu110Val Uncertain significance ★ ⚠ same residue
NPHP3 p.Leu110= Likely benign ★ same residue
NPHP3 p.Ala1135fs Pathogenic ★★ same condition
NPHP3 p.Glu145fs Pathogenic ★★ same condition
NPHP3 p.Gly1275del Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Leu365fs Pathogenic ★★ same condition
NPHP3 p.Ser611fs 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-leu110del (accessed [today's date]).

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