Is NPHP3 p.Glu330Lys (c.988G>A) pathogenic?

NPHP3 p.Glu330Lys (c.988G>A) is classified Conflicting classifications of pathogenicity in NPHP3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-02-15). AlphaMissense: ambiguous (0.5197); Very rare (popmax 0.00225%, eas); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Glu330Lys (c.988G>A)?

NPHP3 p.Glu330Lys (c.988G>A) is associated with nephronophthisis (ClinVar).

How common is NPHP3 p.Glu330Lys (c.988G>A) in the general population?

NPHP3 p.Glu330Lys (c.988G>A) is very rare (popmax 0.00225%, eas) (gnomAD).

How is Nephronophthisis inherited?

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

What do computational predictors say about NPHP3 p.Glu330Lys (c.988G>A)?

AlphaMissense predicts ambiguous (score 0.5197) — an in-silico prediction, not a clinical call.

NPHP3 p.Glu330Lys

c.988G>A · rs758498695 · VCV216011

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5197 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00225%, eas)

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.5197	ambiguous
REVEL	0.561	indeterminate
SaProt	LLR -6.53	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	27.6	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 0.00225% East Asian · 1/44,372 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00168% 27/1,602,462 alleles · very rare exomes 27/1,450,254 · genomes 0/152,208 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00225%	44,372
South Asian	0.00224%	44,552
European (non-Finnish)	0.00204%	48,905

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.Glu330Lys
Coding: c.988G>A
MANE Select: NM_153240
dbSNP: rs758498695
Type: single nucleotide variant
Location: chr3:132713256 (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-p-glu330lys (accessed [today's date]).

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