Is NPHP4 p.Arg288Cys (c.862C>T) pathogenic?

NPHP4 p.Arg288Cys (c.862C>T) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.063); Very rare (popmax 0.00778%, sas); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Arg288Cys (c.862C>T)?

NPHP4 p.Arg288Cys (c.862C>T) is associated with Inborn genetic diseases, nephronophthisis (ClinVar).

How common is NPHP4 p.Arg288Cys (c.862C>T) in the general population?

NPHP4 p.Arg288Cys (c.862C>T) is very rare (popmax 0.00778%, sas) (gnomAD).

What do computational predictors say about NPHP4 p.Arg288Cys (c.862C>T)?

AlphaMissense predicts likely benign (score 0.063) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg288Cys

c.862C>T · rs372256352 · VCV1410699

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.063 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00778%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.063	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -9.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.8	GERP -4.3
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	15.06	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00778% South Asian · 7/89,954 alleles

Filtering AF 0.00363% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00257%

Overall 0.00255% 41/1,605,394 alleles · very rare exomes 37/1,453,224 · genomes 4/152,170 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00778%	12,851
Admixed American	0.00678%	14,741
African / African-American	0.00668%	14,962
European (non-Finnish)	0.00195%	51,189
Finnishnot grpmax-eligible	0.00164%	61,000
Remaining individualsnot grpmax-eligible	0.00161%	62,292

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.Arg288Cys
Coding: c.862C>T
MANE Select: NM_015102
dbSNP: rs372256352
Type: single nucleotide variant
Location: chr1:5948200 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis

Similar variants

NPHP4 p.Arg288Gly Uncertain significance ★★ ⚠ same residue
NPHP4 p.Arg288His 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.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-arg288cys (accessed [today's date]).

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