Is NPHP4 p.His982fs (c.2940_2944dup) pathogenic?

NPHP4 p.His982fs (c.29402944dup) is classified Pathogenic in NPHP4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-03-26). Very rare (popmax 0.005%, amr); Associated with nephronophthisis.

What condition is associated with NPHP4 p.His982fs (c.2940_2944dup)?

NPHP4 p.His982fs (c.2940_2944dup) is associated with nephronophthisis (ClinVar).

How common is NPHP4 p.His982fs (c.2940_2944dup) in the general population?

NPHP4 p.His982fs (c.2940_2944dup) is very rare (popmax 0.005%, amr) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP4 p.His982fs

c.2940_2944dup · rs398124289 · VCV496917

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

nephronophthisis

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 0.83	GERP 0.83, phastCons 0.053

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,024 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,613,078 alleles · very rare exomes 3/1,460,808 · genomes 0/152,270 · joint denominator

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.His982fs
Coding: c.2940_2944dup
MANE Select: NM_015102
dbSNP: rs398124289
Type: Duplication
Location: chr1:5874973 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 982: 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.His982= Likely benign ★★ same residue
NPHP4 p.Leu970fs Pathogenic/Likely pathogenic ★★ same condition
NPHP4 p.Ser1092fs Pathogenic ★★ same condition
NPHP4 p.Ser251fs Pathogenic ★★ same condition
NPHP4 p.Thr1004fs Pathogenic ★★ same condition
NPHP4 c.1306_1314dup Uncertain significance ★★ same condition
NPHP4 c.3231+7dup Likely benign ★★ same condition
NPHP4 p.Ala1029fs 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-his982fs (accessed [today's date]).

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