Is NPHP3 p.Glu1013Asp (c.3039A>C) pathogenic?

NPHP3 p.Glu1013Asp (c.3039A>C) is classified Uncertain significance in NPHP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-24). AlphaMissense: likely benign (0.2929); Very rare (popmax 0.004%, afr); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Glu1013Asp (c.3039A>C)?

NPHP3 p.Glu1013Asp (c.3039A>C) is associated with nephronophthisis, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Glu1013Asp (c.3039A>C) in the general population?

NPHP3 p.Glu1013Asp (c.3039A>C) is very rare (popmax 0.004%, afr) (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.Glu1013Asp (c.3039A>C)?

AlphaMissense predicts likely benign (score 0.2929) — an in-silico prediction, not a clinical call.

NPHP3 p.Glu1013Asp

c.3039A>C · rs941727035 · VCV1377505

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2929 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.2929	likely benign
REVEL	0.596	indeterminate
SaProt	LLR -7.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.076	GERP -0.68, phastCons 0.97
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	15.78	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,922 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,614,034 alleles · very rare exomes 1/1,461,850 · genomes 2/152,184 · 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.Glu1013Asp
Coding: c.3039A>C
MANE Select: NM_153240
dbSNP: rs941727035
Type: single nucleotide variant
Location: chr3:132688736 (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.Glu1013Gln Uncertain significance ★★ ⚠ same residue
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

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-glu1013asp (accessed [today's date]).

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