Is NPHP4 p.Leu1305= (c.3915C>T) pathogenic?

NPHP4 p.Leu1305= (c.3915C>T) is classified Likely benign in NPHP4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-25). Ultra-rare (popmax 0.0227%, afr); Associated with kidney disorder.

What condition is associated with NPHP4 p.Leu1305= (c.3915C>T)?

NPHP4 p.Leu1305= (c.3915C>T) is associated with kidney disorder, nephronophthisis (ClinVar).

How common is NPHP4 p.Leu1305= (c.3915C>T) in the general population?

NPHP4 p.Leu1305= (c.3915C>T) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

NPHP4 p.Leu1305=

c.3915C>T · rs370424194 · VCV1561661

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Conditions

kidney disorder

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 0.019	GERP -3.2, phastCons 0.5
Overall
CADD	0.591	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0227% African / African-American · 17/74,880 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.00124% 20/1,611,670 alleles · ultra-rare exomes 13/1,459,500 · genomes 7/152,170 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,405
Remaining individualsnot grpmax-eligible	0.00481%	20,797

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.Leu1305=
Coding: c.3915C>T
MANE Select: NM_015102
dbSNP: rs370424194
Type: single nucleotide variant
Location: chr1:5864419 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1305: the 'sufficient for basal bodies localization' region

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

Disease context

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

Also linked: nephronophthisis

Similar variants

NPHP4 p.Leu1305Ile 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.518-2A>G Likely pathogenic ★★ same condition
NPHP4 c.992+2T>C 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-leu1305 (accessed [today's date]).

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