Is NPHP4 p.Leu101= (c.301C>T) pathogenic?

NPHP4 p.Leu101= (c.301C>T) is classified Likely benign in NPHP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-07). Very rare (popmax 0.00179%, amr); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Leu101= (c.301C>T)?

NPHP4 p.Leu101= (c.301C>T) is associated with nephronophthisis (ClinVar).

How common is NPHP4 p.Leu101= (c.301C>T) in the general population?

NPHP4 p.Leu101= (c.301C>T) is very rare (popmax 0.00179%, amr) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP4 p.Leu101=

c.301C>T · rs1489058652 · VCV1622036

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00179%, amr)

Conditions

nephronophthisis

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 -0.22	GERP -1.7, phastCons 0.003
Overall
CADD	4.385	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00179% Admixed American · 1/55,888 alleles

Filtering AF 0.00113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000923%

Overall 0.0014% 22/1,568,164 alleles · very rare exomes 21/1,416,134 · genomes 1/152,030 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00179%	55,888
European (non-Finnish)	0.00174%	57,523
Remaining individualsnot grpmax-eligible	0.00165%	60,492

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.Leu101=
Coding: c.301C>T
MANE Select: NM_015102
dbSNP: rs1489058652
Type: single nucleotide variant
Location: chr1:5969238 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44

Full NPHP4 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

For Nephronophthisis (Orphanet):

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

Similar variants

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
NPHP4 p.Arg1109Ter 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/nphp4-p-leu101 (accessed [today's date]).

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