Is NPHP3 p.Arg1259Gln (c.3776G>A) pathogenic?

NPHP3 p.Arg1259Gln (c.3776G>A) is classified Uncertain significance in NPHP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-08). AlphaMissense: likely benign (0.3255); Very rare (popmax 0.00167%, amr).

How common is NPHP3 p.Arg1259Gln (c.3776G>A) in the general population?

NPHP3 p.Arg1259Gln (c.3776G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about NPHP3 p.Arg1259Gln (c.3776G>A)?

AlphaMissense predicts likely benign (score 0.3255) — an in-silico prediction, not a clinical call.

NPHP3 p.Arg1259Gln

c.3776G>A · rs748465701 · VCV2575788

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3255 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3255	likely benign
REVEL	0.45	indeterminate
SaProt	LLR -6.55	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	29.0	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 0.00167% Admixed American · 1/60,018 alleles

Overall 0.000124% 2/1,613,166 alleles · very rare exomes 2/1,460,910 · genomes 0/152,256 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,586
Admixed Americangrpmax	0.00167%	60,018

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1259Gln
Coding: c.3776G>A
MANE Select: NM_153240
dbSNP: rs748465701
Type: single nucleotide variant
Location: chr3:132682739 (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.Arg1259Ter Pathogenic/Likely 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
NPHP3 p.Arg1125Ter 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-arg1259gln (accessed [today's date]).

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