Is NPHP4 p.Phe447Cys (c.1340T>G) pathogenic?

NPHP4 p.Phe447Cys (c.1340T>G) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-19). AlphaMissense: ambiguous (0.3901); Absent from gnomAD v4.1; Associated with nephronophthisis.

What condition is associated with NPHP4 p.Phe447Cys (c.1340T>G)?

NPHP4 p.Phe447Cys (c.1340T>G) is associated with nephronophthisis (ClinVar).

How common is NPHP4 p.Phe447Cys (c.1340T>G) in the general population?

NPHP4 p.Phe447Cys (c.1340T>G) 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.

What do computational predictors say about NPHP4 p.Phe447Cys (c.1340T>G)?

AlphaMissense predicts ambiguous (score 0.3901) — an in-silico prediction, not a clinical call.

NPHP4 p.Phe447Cys

c.1340T>G · rs1646081863 · VCV1040108

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3901 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.3901	ambiguous
REVEL	0.527	indeterminate
SaProt	LLR -10.15	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -2.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

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

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.Phe447Cys
Coding: c.1340T>G
MANE Select: NM_015102
dbSNP: rs1646081863
Type: single nucleotide variant
Location: chr1:5927750 (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-phe447cys (accessed [today's date]).

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