Is NPHP3 p.Glu435del (c.1304_1306del) pathogenic?

NPHP3 p.Glu435del (c.13041306del) is classified Conflicting classifications of pathogenicity in NPHP3 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-08). Very rare (popmax 0.00275%, afr); Associated with Joubert syndrome and related disorders.

What condition is associated with NPHP3 p.Glu435del (c.1304_1306del)?

NPHP3 p.Glu435del (c.1304_1306del) is associated with Joubert syndrome and related disorders, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Glu435del (c.1304_1306del) in the general population?

NPHP3 p.Glu435del (c.1304_1306del) is very rare (popmax 0.00275%, afr) (gnomAD).

NPHP3 p.Glu435del

c.1304_1306del · rs1456714047 · VCV462722

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00275%, afr)

Conditions

Joubert syndrome and related disorders

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 5.9	GERP 1.9, phastCons 1
Overall
CADD	18.89	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00275% African / African-American · 2/72,848 alleles

Filtering AF 0.000456% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000171%

Overall 0.000331% 5/1,509,818 alleles · very rare exomes 4/1,357,672 · genomes 1/152,146 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00275%	36,424
South Asian	0.00113%	88,424
European (non-Finnish)	0.000184%	543,301

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.Glu435del
Coding: c.1304_1306del
MANE Select: NM_153240
dbSNP: rs1456714047
Type: Deletion
Location: chr3:132705784 (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

Joubert syndrome and related disorders — 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 nephronophthisis

Similar variants

NPHP3 c.1888-7_1893del Pathogenic/Likely pathogenic ★★ same condition
NPHP3 c.3570+1del Likely pathogenic ★★ same condition
NPHP3 p.Arg157fs Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Glu90_Tyr91insTer Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.His559fs Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Phe1001fs Pathogenic ★★ same condition
NPHP3 p.Thr136fs Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Val363fs 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/nphp3-p-glu435del (accessed [today's date]).

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