Is NPHP4 c.*128A>C pathogenic?

NPHP4 c.128A>C is classified Benign in NPHP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Low-frequency (popmax 3.88%, afr); Associated with Senior-Loken syndrome 4.

What condition is associated with NPHP4 c.*128A>C?

NPHP4 c.*128A>C is associated with Senior-Loken syndrome 4, nephronophthisis 4 (ClinVar).

How common is NPHP4 c.*128A>C in the general population?

NPHP4 c.*128A>C is low-frequency (popmax 3.88%, afr) (gnomAD).

How is Senior-Loken syndrome inherited?

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

NPHP4 c.*128A>C

rs116747881 · VCV297782

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

low-frequency (popmax 3.88%, afr)

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 -0.49	GERP -3.2
Overall
CADD	0.044	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.88% African / African-American · 2,444/63,062 alleles

Filtering AF 3.75% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.7%

Overall 0.275% 2,695/980,112 alleles · low-frequency exomes 1,058/827,858 · genomes 1,637/152,254 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.88%	26
Remaining individualsnot grpmax-eligible	0.289%	346
Admixed American	0.192%	520
Middle Eastern	0.109%	914
European (non-Finnish)	0.0034%	29,407

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
Coding: c.*128A>C
MANE Select: NM_015102
dbSNP: rs116747881
Type: single nucleotide variant
Location: chr1:5863137 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44

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

For Senior-Loken syndrome (Orphanet):

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

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 p.Arg1109Ter 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-c-star-128a-c (accessed [today's date]).

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