Is NPHP4 p.Arg857Cys (c.2569C>T) pathogenic?

NPHP4 p.Arg857Cys (c.2569C>T) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-04). AlphaMissense: likely benign (0.0768); Ultra-rare (popmax 0.0317%, amr); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Arg857Cys (c.2569C>T)?

NPHP4 p.Arg857Cys (c.2569C>T) is associated with nephronophthisis, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Arg857Cys (c.2569C>T) in the general population?

NPHP4 p.Arg857Cys (c.2569C>T) is ultra-rare (popmax 0.0317%, amr) (gnomAD).

How is Nephronophthisis inherited?

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

What do computational predictors say about NPHP4 p.Arg857Cys (c.2569C>T)?

AlphaMissense predicts likely benign (score 0.0768) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg857Cys

c.2569C>T · rs372688518 · VCV288104

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0768 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.0768	likely benign
REVEL	0.305	indeterminate
SaProt	LLR -7.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -3.8
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	19.62	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0317% Admixed American · 19/59,970 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00632% 102/1,613,550 alleles · ultra-rare exomes 88/1,461,360 · genomes 14/152,190 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0317%	3,156
Remaining individualsnot grpmax-eligible	0.0192%	5,205
East Asian	0.00668%	14,962
European (non-Finnish)	0.00551%	18,150
African / African-American	0.00267%	37,465
South Asian	0.0011%	90,970

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.Arg857Cys
Coding: c.2569C>T
MANE Select: NM_015102
dbSNP: rs372688518
Type: single nucleotide variant
Location: chr1:5880156 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 857: 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 p.Arg857His Uncertain significance ★★ ⚠ 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
NPHP4 c.517+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.518-2A>G 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-arg857cys (accessed [today's date]).

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