Is NPHP4 p.Arg1259= (c.3777G>A) pathogenic?

NPHP4 p.Arg1259= (c.3777G>A) is classified Benign/Likely benign in NPHP4 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-15). Rare (popmax 0.506%, sas); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Arg1259= (c.3777G>A)?

NPHP4 p.Arg1259= (c.3777G>A) is associated with nephronophthisis, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Arg1259= (c.3777G>A) in the general population?

NPHP4 p.Arg1259= (c.3777G>A) is rare (popmax 0.506%, sas) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP4 p.Arg1259=

c.3777G>A · rs369566680 · VCV287096

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.506%, sas)

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.78 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.8	GERP 1.7, phastCons 1
Overall
CADD	14.32	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.506% South Asian · 461/91,078 alleles

Filtering AF 0.468% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.453%

Overall 0.0532% 859/1,613,702 alleles · rare exomes 809/1,461,346 · genomes 50/152,356 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.506%	198
Middle Eastern	0.248%	404
Remaining individualsnot grpmax-eligible	0.0736%	1,358
Ashkenazi Jewishnot grpmax-eligible	0.0574%	1,741
European (non-Finnish)	0.0251%	3,986
Admixed American	0.025%	4,001
Finnishnot grpmax-eligible	0.011%	9,113
East Asian	0.00223%	44,884
African / African-American	0.00133%	75,062

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.Arg1259=
Coding: c.3777G>A
MANE Select: NM_015102
dbSNP: rs369566680
Type: single nucleotide variant
Location: chr1:5865141 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1259: 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

Also linked: nephronophthisis 4 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 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.517+1G>A 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-arg1259 (accessed [today's date]).

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