Is NPHP4 p.Leu1391Ter (c.4172T>A) pathogenic?

NPHP4 p.Leu1391Ter (c.4172T>A) is classified Uncertain significance in NPHP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). Absent from gnomAD v4.1; Associated with nephronophthisis.

What condition is associated with NPHP4 p.Leu1391Ter (c.4172T>A)?

NPHP4 p.Leu1391Ter (c.4172T>A) is associated with nephronophthisis (ClinVar).

How common is NPHP4 p.Leu1391Ter (c.4172T>A) in the general population?

NPHP4 p.Leu1391Ter (c.4172T>A) is absent from gnomAD v4.1 (gnomAD).

How is Nephronophthisis inherited?

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

NPHP4 p.Leu1391Ter

c.4172T>A · rs2100357134 · VCV1486799

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (30 of 30) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	Δ0.24	acceptor loss, 5 bp away · masked 0 · deltas
Pangolin	Δ0.34	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NPHP4
Protein: p.Leu1391Ter
Coding: c.4172T>A
MANE Select: NM_015102
dbSNP: rs2100357134
Type: single nucleotide variant
Location: chr1:5863374 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1391: the 'sufficient for basal bodies localization' region

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 p.Leu1391= Likely benign ★ 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-leu1391ter (accessed [today's date]).

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