Is NPHP1 p.Arg530Gln (c.1589G>A) pathogenic?

NPHP1 p.Arg530Gln (c.1589G>A) is classified Uncertain significance in NPHP1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-25). AlphaMissense: ambiguous (0.3678); Ultra-rare (popmax 0.0134%, eas); Associated with nephronophthisis.

What condition is associated with NPHP1 p.Arg530Gln (c.1589G>A)?

NPHP1 p.Arg530Gln (c.1589G>A) is associated with nephronophthisis, nephronophthisis 1, Senior-Loken syndrome 1 (ClinVar).

How common is NPHP1 p.Arg530Gln (c.1589G>A) in the general population?

NPHP1 p.Arg530Gln (c.1589G>A) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

How is Nephronophthisis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NPHP1 p.Arg530Gln (c.1589G>A)?

AlphaMissense predicts ambiguous (score 0.3678) — an in-silico prediction, not a clinical call.

NPHP1 p.Arg530Gln

c.1589G>A · rs534052463 · VCV1303342

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3678 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.3678	ambiguous
REVEL	0.78	moderately pathogenic-leaning
SaProt	LLR -12.40	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP -0.11, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R585Q vs ClinVar R530Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,842 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00167% 27/1,613,202 alleles · ultra-rare exomes 18/1,461,110 · genomes 9/152,092 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,474
African / African-American	0.00934%	10,710
Remaining individualsnot grpmax-eligible	0.0032%	31,238
Admixed American	0.00167%	59,982
South Asian	0.0011%	91,024
European (non-Finnish)	0.000848%	117,938

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: NPHP1
Protein: p.Arg530Gln
Coding: c.1589G>A
MANE Select: NM_001128178
dbSNP: rs534052463
Type: single nucleotide variant
Location: chr2:110131732 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB

Full NPHP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephronophthisis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 1 Senior-Loken syndrome 1 Joubert syndrome with renal defect

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

NPHP1 p.Arg530Ter Pathogenic ★★ same residue
NPHP1 c.1083+1G>A Likely pathogenic ★★ same condition
NPHP1 c.1270-1G>A Pathogenic ★★ same condition
NPHP1 c.1270-2A>G Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.143+1G>C Likely pathogenic ★★ same condition
NPHP1 c.144-1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.1716+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.329+1G>A Pathogenic/Likely pathogenic ★★ 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/nphp1-p-arg530gln (accessed [today's date]).

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