Is NPHP3 p.Glu26Lys (c.76G>A) pathogenic?

NPHP3 p.Glu26Lys (c.76G>A) is classified Uncertain significance in NPHP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-12-08). AlphaMissense: ambiguous (0.342); Very rare (popmax 0.000598%, nfe); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Glu26Lys (c.76G>A)?

NPHP3 p.Glu26Lys (c.76G>A) is associated with nephronophthisis, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Glu26Lys (c.76G>A) in the general population?

NPHP3 p.Glu26Lys (c.76G>A) is very rare (popmax 0.000598%, nfe) (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.Glu26Lys (c.76G>A)?

AlphaMissense predicts ambiguous (score 0.342) — an in-silico prediction, not a clinical call.

NPHP3 p.Glu26Lys

c.76G>A · rs1465502034 · VCV1386222

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.342 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000598%, nfe)

Conditions

nephronophthisis

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.342	ambiguous
REVEL	0.594	indeterminate
SaProt	LLR -7.64	tolerated
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.3	GERP 1.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	24.6	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 0.000598% European (non-Finnish) · 7/1,171,410 alleles

Filtering AF 0.000249% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00016%

Overall 0.000443% 7/1,578,498 alleles · very rare exomes 7/1,426,410 · genomes 0/152,088 · joint denominator

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.Glu26Lys
Coding: c.76G>A
MANE Select: NM_153240
dbSNP: rs1465502034
Type: single nucleotide variant
Location: chr3:132722280 (GRCh38)

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)

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-glu26lys (accessed [today's date]).

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