Is NPHP3 p.Leu1096Pro (c.3287T>C) pathogenic?

NPHP3 p.Leu1096Pro (c.3287T>C) is classified Conflicting classifications of pathogenicity in NPHP3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-11-25). AlphaMissense: likely pathogenic (0.9957); Very rare (popmax 0.00153%, nfe); Associated with renal-hepatic-pancreatic dysplasia 1.

What condition is associated with NPHP3 p.Leu1096Pro (c.3287T>C)?

NPHP3 p.Leu1096Pro (c.3287T>C) is associated with renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome, nephronophthisis 3 (ClinVar).

How common is NPHP3 p.Leu1096Pro (c.3287T>C) in the general population?

NPHP3 p.Leu1096Pro (c.3287T>C) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about NPHP3 p.Leu1096Pro (c.3287T>C)?

AlphaMissense predicts likely pathogenic (score 0.9957) — an in-silico prediction, not a clinical call.

NPHP3 p.Leu1096Pro

c.3287T>C · rs777276873 · VCV562245

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9957 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

renal-hepatic-pancreatic dysplasia 1

Computational evidence

Protein change
AlphaMissense	0.9957	likely pathogenic · top 1% in NPHP3
REVEL	0.982	strongly pathogenic-leaning
SaProt	LLR -16.89	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00153% European (non-Finnish) · 18/1,179,828 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00118% 19/1,613,816 alleles · very rare exomes 17/1,461,612 · genomes 2/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00153%	65,546
African / African-American	0.00133%	74,930

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.Leu1096Pro
Coding: c.3287T>C
MANE Select: NM_153240
dbSNP: rs777276873
Type: single nucleotide variant
Location: chr3:132686302 (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

renal-hepatic-pancreatic dysplasia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: NPHP3-related Meckel-like syndrome nephronophthisis 3

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.520-1G>T Pathogenic ★★ same condition
NPHP3 c.823+1G>T 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

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-leu1096pro (accessed [today's date]).

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