Is NPHP3 p.Val528Met (c.1582G>A) pathogenic?

NPHP3 p.Val528Met (c.1582G>A) is classified Uncertain significance in NPHP3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-12-21). AlphaMissense: likely pathogenic (0.5642); Very rare (popmax 0.00229%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NPHP3 p.Val528Met (c.1582G>A)?

NPHP3 p.Val528Met (c.1582G>A) is associated with Inborn genetic diseases (ClinVar).

How common is NPHP3 p.Val528Met (c.1582G>A) in the general population?

NPHP3 p.Val528Met (c.1582G>A) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about NPHP3 p.Val528Met (c.1582G>A)?

AlphaMissense predicts likely pathogenic (score 0.5642) — an in-silico prediction, not a clinical call.

NPHP3 p.Val528Met

c.1582G>A · rs373000939 · VCV2252154

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5642 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5642	likely pathogenic
REVEL	0.504	indeterminate
SaProt	LLR -11.32	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00229% European (non-Finnish) · 27/1,179,740 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.0018% 29/1,613,632 alleles · very rare exomes 29/1,461,546 · genomes 0/152,086 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00229%	43,694
South Asian	0.0022%	45,540

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.Val528Met
Coding: c.1582G>A
MANE Select: NM_153240
dbSNP: rs373000939
Type: single nucleotide variant
Location: chr3:132701476 (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-val528met (accessed [today's date]).

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