Is NPHP4 p.Arg870fs (c.2598_2607dup) pathogenic?

NPHP4 p.Arg870fs (c.25982607dup) is classified Likely pathogenic in NPHP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-01). Very rare (popmax 0.00415%, nfe); Associated with retinitis pigmentosa.

What condition is associated with NPHP4 p.Arg870fs (c.2598_2607dup)?

NPHP4 p.Arg870fs (c.2598_2607dup) is associated with retinitis pigmentosa (ClinVar).

How common is NPHP4 p.Arg870fs (c.2598_2607dup) in the general population?

NPHP4 p.Arg870fs (c.2598_2607dup) is very rare (popmax 0.00415%, nfe) (gnomAD).

How is Retinitis pigmentosa inherited?

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

NPHP4 p.Arg870fs

c.2598_2607dup · rs752910449 · VCV1297092

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Conditions

retinitis pigmentosa

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 19 of 30
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.91	GERP 0.7, phastCons 0.002
Overall
CADD	24.3	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

Grpmax group 0.00415% European (non-Finnish) · 49/1,179,774 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00322% 52/1,613,580 alleles · very rare exomes 50/1,461,422 · genomes 2/152,158 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00415%	24,077
Remaining individualsnot grpmax-eligible	0.0032%	31,230
African / African-American	0.00133%	74,920

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.Arg870fs
Coding: c.2598_2607dup
MANE Select: NM_015102
dbSNP: rs752910449
Type: Duplication
Location: chr1:5880117 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 870: the 'sufficient for basal bodies localization' region

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

Disease context

retinitis pigmentosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

NPHP4 p.Arg870Lys Uncertain significance ★ ⚠ same residue
NPHP4 p.Glu257fs Likely pathogenic ★ same condition
NPHP4 p.His982fs Pathogenic ★★ same type
NPHP4 p.Leu970fs Pathogenic/Likely pathogenic ★★ same type
NPHP4 p.Ser1092fs Pathogenic ★★ same type
NPHP4 p.Ser251fs Pathogenic ★★ same type
NPHP4 p.Thr1004fs Pathogenic ★★ same type
NPHP4 c.1306_1314dup Uncertain significance ★★ same type

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-arg870fs (accessed [today's date]).

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