Is NPHP1 p.Lys539= (c.1617A>G) pathogenic?

NPHP1 p.Lys539= (c.1617A>G) is classified Conflicting classifications of pathogenicity in NPHP1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-11-05). Very rare (popmax 0.00801%, afr); Associated with Joubert syndrome with renal defect.

What condition is associated with NPHP1 p.Lys539= (c.1617A>G)?

NPHP1 p.Lys539= (c.1617A>G) is associated with Joubert syndrome with renal defect, nephronophthisis 1, Senior-Loken syndrome 1 (ClinVar).

How common is NPHP1 p.Lys539= (c.1617A>G) in the general population?

NPHP1 p.Lys539= (c.1617A>G) is very rare (popmax 0.00801%, afr) (gnomAD).

NPHP1 p.Lys539=

c.1617A>G · rs1266229950 · VCV1434973

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Conditions

Joubert syndrome with renal defect

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -1.6, phastCons 1
Overall
CADD	7.53	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00801% African / African-American · 6/74,908 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000372% 6/1,612,460 alleles · very rare exomes 3/1,460,254 · genomes 3/152,206 · joint denominator

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.Lys539=
Coding: c.1617A>G
MANE Select: NM_001128178
dbSNP: rs1266229950
Type: single nucleotide variant
Location: chr2:110131704 (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

Joubert syndrome with renal defect — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 1 Senior-Loken syndrome 1 nephronophthisis

Similar variants

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
NPHP1 c.522+1G>A 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-lys539 (accessed [today's date]).

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