Is NPHP3 p.Arg512Gly (c.1534C>G) pathogenic?

NPHP3 p.Arg512Gly (c.1534C>G) is classified Uncertain significance in NPHP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-26). AlphaMissense: likely benign (0.2507); Absent from gnomAD v4.1; Associated with NPHP3-related Meckel-like syndrome.

What condition is associated with NPHP3 p.Arg512Gly (c.1534C>G)?

NPHP3 p.Arg512Gly (c.1534C>G) is associated with NPHP3-related Meckel-like syndrome, renal-hepatic-pancreatic dysplasia 1, nephronophthisis 3 (ClinVar).

How common is NPHP3 p.Arg512Gly (c.1534C>G) in the general population?

NPHP3 p.Arg512Gly (c.1534C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NPHP3 p.Arg512Gly (c.1534C>G)?

AlphaMissense predicts likely benign (score 0.2507) — an in-silico prediction, not a clinical call.

NPHP3 p.Arg512Gly

c.1534C>G · VCV3588553

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2507 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

NPHP3-related Meckel-like syndrome

Computational evidence

Protein change
AlphaMissense	0.2507	likely benign
REVEL	0.508	indeterminate
SaProt	LLR -9.35	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 9.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	26.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NPHP3
Protein: p.Arg512Gly
Coding: c.1534C>G
MANE Select: NM_153240
Type: single nucleotide variant
Location: chr3:132701524 (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

Also linked: renal-hepatic-pancreatic dysplasia 1 nephronophthisis 3

Similar variants

NPHP3 p.Arg512His Uncertain significance ★★ ⚠ same residue
NPHP3 p.Arg512Cys 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

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-arg512gly (accessed [today's date]).

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