Is NPHP4 p.Arg390Cys (c.1168C>T) pathogenic?

NPHP4 p.Arg390Cys (c.1168C>T) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-05-08). AlphaMissense: likely benign (0.3224); Ultra-rare (popmax 0.01%, amr); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Arg390Cys (c.1168C>T)?

NPHP4 p.Arg390Cys (c.1168C>T) is associated with Inborn genetic diseases, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Arg390Cys (c.1168C>T) in the general population?

NPHP4 p.Arg390Cys (c.1168C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about NPHP4 p.Arg390Cys (c.1168C>T)?

AlphaMissense predicts likely benign (score 0.3224) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg390Cys

c.1168C>T · rs748941493 · VCV1425961

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3224 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3224	likely benign
REVEL	0.736	pathogenic-leaning
SaProt	LLR -5.29	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	28.9	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 0.01% Admixed American · 6/60,000 alleles

Filtering AF 0.00766% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00708%

Overall 0.0075% 121/1,613,520 alleles · ultra-rare exomes 115/1,461,340 · genomes 6/152,180 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,000
European (non-Finnish)	0.00907%	11,027
Remaining individualsnot grpmax-eligible	0.00801%	12,489
African / African-American	0.004%	24,973

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.Arg390Cys
Coding: c.1168C>T
MANE Select: NM_015102
dbSNP: rs748941493
Type: single nucleotide variant
Location: chr1:5933281 (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 4 Senior-Loken syndrome 4 nephronophthisis

Similar variants

NPHP4 p.Arg390His Conflicting classifications of pathogenicity ★ ⚠ same residue
NPHP4 p.Arg390= Likely benign ★ same residue
NPHP4 p.Arg390Leu 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

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-arg390cys (accessed [today's date]).

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