Is NPHP3 p.Leu1007Arg (c.3020T>G) pathogenic?

NPHP3 p.Leu1007Arg (c.3020T>G) is classified Likely pathogenic in NPHP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-01). AlphaMissense: likely pathogenic (0.8192); Very rare (popmax 0.000424%, nfe).

How common is NPHP3 p.Leu1007Arg (c.3020T>G) in the general population?

NPHP3 p.Leu1007Arg (c.3020T>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about NPHP3 p.Leu1007Arg (c.3020T>G)?

AlphaMissense predicts likely pathogenic (score 0.8192) — an in-silico prediction, not a clinical call.

NPHP3 p.Leu1007Arg

c.3020T>G · rs1939225674 · VCV2498938

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8192 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8192	likely pathogenic ✓ concordant with ClinVar
REVEL	0.873	moderately pathogenic-leaning
SaProt	LLR -11.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	26.9	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 0.000424% European (non-Finnish) · 5/1,180,006 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,614,158 alleles · very rare exomes 6/1,461,860 · genomes 0/152,298 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)grpmax	0.000424%	236,001

Remaining individuals 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.Leu1007Arg
Coding: c.3020T>G
MANE Select: NM_153240
dbSNP: rs1939225674
Type: single nucleotide variant
Location: chr3:132688755 (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 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
NPHP3 p.Arg1259Ter Pathogenic/Likely 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-leu1007arg (accessed [today's date]).

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