Is NPHP4 p.Arg342Cys (c.1024C>T) pathogenic?

NPHP4 p.Arg342Cys (c.1024C>T) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.1078); Low-frequency (popmax 1.54%, mid); Associated with kidney disorder.

What condition is associated with NPHP4 p.Arg342Cys (c.1024C>T)?

NPHP4 p.Arg342Cys (c.1024C>T) is associated with kidney disorder, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Arg342Cys (c.1024C>T) in the general population?

NPHP4 p.Arg342Cys (c.1024C>T) is low-frequency (popmax 1.54%, mid) (gnomAD).

What do computational predictors say about NPHP4 p.Arg342Cys (c.1024C>T)?

AlphaMissense predicts likely benign (score 0.1078) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg342Cys

c.1024C>T · rs190940697 · VCV281181

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1078 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.54%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

kidney disorder

Computational evidence

Protein change
AlphaMissense	0.1078	likely benign
REVEL	0.765	pathogenic-leaning
SaProt	LLR -7.67	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 7.3	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	26.6	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 1.54% Middle Eastern · 93/6,036 alleles

Filtering AF 1.29% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.19%

Overall 0.117% 1,890/1,613,796 alleles · low-frequency exomes 1,685/1,461,588 · genomes 205/152,208 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.54%	65
South Asian	0.58%	172
Admixed American	0.302%	332
Remaining individualsnot grpmax-eligible	0.181%	553
Ashkenazi Jewishnot grpmax-eligible	0.138%	722
European (non-Finnish)	0.0772%	1,295
African / African-American	0.0213%	4,687
East Asian	0.00892%	11,215
Finnishnot grpmax-eligible	0.00469%	21,332

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.Arg342Cys
Coding: c.1024C>T
MANE Select: NM_015102
dbSNP: rs190940697
Type: single nucleotide variant
Location: chr1:5947199 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 342: a UniProt-annotated variant site (in nphp4)

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

Disease context

kidney disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 4 Senior-Loken syndrome 4 nephronophthisis

Similar variants

NPHP4 p.Arg342His 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-arg342cys (accessed [today's date]).

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