Is NPHP4 p.Arg1247= (c.3741C>A) pathogenic?

NPHP4 p.Arg1247= (c.3741C>A) is classified Likely benign in NPHP4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-10-24). Very rare (popmax 0.00667%, amr); Associated with Senior-Loken syndrome 4.

What condition is associated with NPHP4 p.Arg1247= (c.3741C>A)?

NPHP4 p.Arg1247= (c.3741C>A) is associated with Senior-Loken syndrome 4, nephronophthisis 4, nephronophthisis (ClinVar).

How common is NPHP4 p.Arg1247= (c.3741C>A) in the general population?

NPHP4 p.Arg1247= (c.3741C>A) is very rare (popmax 0.00667%, amr) (gnomAD).

How is Senior-Loken syndrome inherited?

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

NPHP4 p.Arg1247=

c.3741C>A · rs890957347 · VCV1666204

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

Senior-Loken syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -1.5, phastCons 1
Overall
CADD	7.301	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,000 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000372% 6/1,613,076 alleles · very rare exomes 6/1,460,716 · genomes 0/152,360 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,000
Remaining individualsnot grpmax-eligible	0.0016%	62,466
European (non-Finnish)	8.48e-05%	1,179,592

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.Arg1247=
Coding: c.3741C>A
MANE Select: NM_015102
dbSNP: rs890957347
Type: single nucleotide variant
Location: chr1:5865177 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1247: the 'sufficient for basal bodies localization' region

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

Disease context

Senior-Loken syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 4 nephronophthisis

For Senior-Loken syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

NPHP4 p.Arg1247Cys Uncertain significance ★★ ⚠ same residue
NPHP4 p.Arg1247His Uncertain significance ★★ ⚠ same residue
NPHP4 p.Arg1247fs Likely pathogenic ★ same residue
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

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-arg1247 (accessed [today's date]).

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