Is NPHP3 p.Pro256Arg (c.767C>G) pathogenic?

NPHP3 p.Pro256Arg (c.767C>G) is classified Uncertain significance in NPHP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-09). AlphaMissense: likely pathogenic (0.6278); Absent from gnomAD v4.1.

How common is NPHP3 p.Pro256Arg (c.767C>G) in the general population?

NPHP3 p.Pro256Arg (c.767C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NPHP3 p.Pro256Arg (c.767C>G)?

AlphaMissense predicts likely pathogenic (score 0.6278) — an in-silico prediction, not a clinical call.

NPHP3 p.Pro256Arg

c.767C>G · rs374171796 · VCV2682845

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6278 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6278	likely pathogenic
REVEL	0.657	pathogenic-leaning
SaProt	LLR -6.19	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.61	donor gain · deltas
Pangolin	Δ0.46	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 10	GERP 2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	34.0	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

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.Pro256Arg
Coding: c.767C>G
MANE Select: NM_153240
dbSNP: rs374171796
Type: single nucleotide variant
Location: chr3:132716813 (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

Similar variants

NPHP3 p.Pro256Leu Uncertain significance ★ same residue
NPHP3 p.Pro256fs Pathogenic ★ same residue
NPHP3 c.1985+1G>A Pathogenic/Likely pathogenic ★★ same type
NPHP3 c.3201+1G>T Likely pathogenic ★★ same type
NPHP3 c.393+1G>C Likely pathogenic ★★ same type
NPHP3 c.520-1G>T Pathogenic ★★ same type
NPHP3 c.823+1G>T Likely pathogenic ★★ same type
NPHP3 c.958-2A>G Pathogenic ★★ same type

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-pro256arg (accessed [today's date]).

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