Is NPHP3 p.Glu180Gln (c.538G>C) pathogenic?

NPHP3 p.Glu180Gln (c.538G>C) is classified Uncertain significance in NPHP3 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-08-10). AlphaMissense: likely pathogenic (0.9479); Very rare (popmax 0.00237%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NPHP3 p.Glu180Gln (c.538G>C)?

NPHP3 p.Glu180Gln (c.538G>C) is associated with Inborn genetic diseases (ClinVar).

How common is NPHP3 p.Glu180Gln (c.538G>C) in the general population?

NPHP3 p.Glu180Gln (c.538G>C) is very rare (popmax 0.00237%, nfe) (gnomAD).

What do computational predictors say about NPHP3 p.Glu180Gln (c.538G>C)?

AlphaMissense predicts likely pathogenic (score 0.9479) — an in-silico prediction, not a clinical call.

NPHP3 p.Glu180Gln

c.538G>C · rs150540012 · VCV2222750

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9479 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9479	likely pathogenic · top 7% in NPHP3
REVEL	0.536	indeterminate
SaProt	LLR -8.23	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	26.8	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 0.00237% European (non-Finnish) · 28/1,178,982 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00186% 30/1,611,378 alleles · very rare exomes 28/1,459,212 · genomes 2/152,166 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,157
European (non-Finnish)grpmax	0.00237%	42,107

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.Glu180Gln
Coding: c.538G>C
MANE Select: NM_153240
dbSNP: rs150540012
Type: single nucleotide variant
Location: chr3:132719126 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NPHP3 p.Ala1203Val Uncertain significance ★★ ⚠ same condition
NPHP3 p.Arg605Cys Uncertain significance ★★ ⚠ same condition
NPHP3 p.Arg705His Uncertain significance ★★ ⚠ same condition
NPHP3 p.Arg756Trp Uncertain significance ★★ ⚠ same condition
NPHP3 p.Asn1097Ser Uncertain significance ★★ ⚠ same condition
NPHP3 p.Asn218Ser Uncertain significance ★★ ⚠ same condition
NPHP3 p.Asn776Ser Uncertain significance ★★ ⚠ same condition
NPHP3 p.Gly235Arg Uncertain significance ★★ ⚠ 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-glu180gln (accessed [today's date]).

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