Is NPHP4 p.Leu759Phe (c.2275C>T) pathogenic?

NPHP4 p.Leu759Phe (c.2275C>T) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-24). AlphaMissense: likely benign (0.285); Ultra-rare (popmax 0.0155%, sas); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Leu759Phe (c.2275C>T)?

NPHP4 p.Leu759Phe (c.2275C>T) is associated with Inborn genetic diseases, nephronophthisis, inherited retinal dystrophy (ClinVar).

How common is NPHP4 p.Leu759Phe (c.2275C>T) in the general population?

NPHP4 p.Leu759Phe (c.2275C>T) is ultra-rare (popmax 0.0155%, sas) (gnomAD).

What do computational predictors say about NPHP4 p.Leu759Phe (c.2275C>T)?

AlphaMissense predicts likely benign (score 0.285) — an in-silico prediction, not a clinical call.

NPHP4 p.Leu759Phe

c.2275C>T · rs749757832 · VCV2058318

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.285 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0155%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.285	likely benign
REVEL	0.625	indeterminate
SaProt	LLR -9.63	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0155% South Asian · 14/90,572 alleles

Filtering AF 0.00934% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00739%

Overall 0.0018% 29/1,610,586 alleles · ultra-rare exomes 25/1,458,382 · genomes 4/152,204 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0155%	6,469
Remaining individualsnot grpmax-eligible	0.00321%	31,157
European (non-Finnish)	0.0011%	90,633

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.Leu759Phe
Coding: c.2275C>T
MANE Select: NM_015102
dbSNP: rs749757832
Type: single nucleotide variant
Location: chr1:5890897 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis inherited retinal dystrophy

Similar variants

NPHP4 p.Leu759= 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-leu759phe (accessed [today's date]).

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