Is NPHP4 p.Ala983fs (c.2945_2946dup) pathogenic?

NPHP4 p.Ala983fs (c.29452946dup) is classified Likely pathogenic in NPHP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-02). Associated with nephronophthisis 4.

What condition is associated with NPHP4 p.Ala983fs (c.2945_2946dup)?

NPHP4 p.Ala983fs (c.2945_2946dup) is associated with nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How is Nephronophthisis inherited?

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

NPHP4 p.Ala983fs

c.2945_2946dup · VCV3586390

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

nephronophthisis 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 21 of 30
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.1	GERP 0.65, phastCons 1

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

Variant & gene context

Gene: NPHP4
Protein: p.Ala983fs
Coding: c.2945_2946dup
MANE Select: NM_015102
Type: Duplication
Location: chr1:5874971 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 983: the 'sufficient for basal bodies localization' region

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

Disease context

nephronophthisis 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Senior-Loken syndrome 4

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP4 p.Leu970fs Pathogenic/Likely pathogenic ★★ same condition
NPHP4 p.Ser251fs Pathogenic ★★ same condition
NPHP4 c.1306_1314dup Uncertain significance ★★ same condition
NPHP4 c.3231+7dup Likely benign ★★ same condition
NPHP4 p.His873fs Pathogenic ★ same condition
NPHP4 p.His999fs Likely pathogenic ★ same condition
NPHP4 c.1503+2dup Uncertain significance ★ same condition
NPHP4 p.Ala983Pro Uncertain significance ★ ⚠ same residue

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-ala983fs (accessed [today's date]).

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