Is NPHP4 p.Leu490= (c.1470C>T) pathogenic?

NPHP4 p.Leu490= (c.1470C>T) is classified Benign/Likely benign in NPHP4 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-03). Common (popmax 10.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Senior-Loken syndrome 4.

What condition is associated with NPHP4 p.Leu490= (c.1470C>T)?

NPHP4 p.Leu490= (c.1470C>T) is associated with Senior-Loken syndrome 4, kidney disorder, nephronophthisis 4 (ClinVar).

How is Senior-Loken syndrome inherited?

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

NPHP4 p.Leu490=

Q: How common is NPHP4 p.Leu490= (c.1470C>T) in the general population?

NPHP4 p.Leu490= (c.1470C>T) is common (popmax 10.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1470C>T · rs12116997 · VCV260543

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 10.4%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Senior-Loken syndrome 4

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 -7.3	GERP -3.4
Overall
CADD	0.108	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.4% African / African-American · 7,765/74,812 alleles

Filtering AF 10.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.1%

Overall 2.91% 46,738/1,603,376 alleles · common exomes 39,767/1,451,210 · genomes 6,971/152,166 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.4%	10
Amishnot grpmax-eligible	6.81%	15
Finnishnot grpmax-eligible	4.18%	24
Middle Eastern	3.52%	28
Ashkenazi Jewishnot grpmax-eligible	3.29%	30
South Asian	3.17%	32
Remaining individualsnot grpmax-eligible	3.03%	33
European (non-Finnish)	2.52%	40
Admixed American	1.34%	74
East Asian	0.0135%	7,425

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: NPHP4
Protein: p.Leu490=
Coding: c.1470C>T
MANE Select: NM_015102
dbSNP: rs12116997
Type: single nucleotide variant
Location: chr1:5909185 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 490: the 'disordered' region

Full NPHP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Senior-Loken syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: kidney disorder nephronophthisis 4 nephronophthisis

For Senior-Loken syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

NPHP4 p.Leu490Pro Uncertain significance ★ ⚠ same residue
NPHP4 c.2304+1G>A Pathogenic ★★ same condition
NPHP4 c.2611+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.2611+1G>C Pathogenic ★★ same condition
NPHP4 c.3644+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.3644+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.517+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.518-2A>G 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/nphp4-p-leu490 (accessed [today's date]).

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