Is NPHP4 p.Arg1301Cys (c.3901C>T) pathogenic?

NPHP4 p.Arg1301Cys (c.3901C>T) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-02). AlphaMissense: likely benign (0.148); Very rare (popmax 0.00433%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Arg1301Cys (c.3901C>T)?

NPHP4 p.Arg1301Cys (c.3901C>T) is associated with Inborn genetic diseases, nephronophthisis (ClinVar).

How common is NPHP4 p.Arg1301Cys (c.3901C>T) in the general population?

NPHP4 p.Arg1301Cys (c.3901C>T) is very rare (popmax 0.00433%, nfe) (gnomAD).

What do computational predictors say about NPHP4 p.Arg1301Cys (c.3901C>T)?

AlphaMissense predicts likely benign (score 0.148) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg1301Cys

c.3901C>T · rs766610686 · VCV1500794

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.148 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00433%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.148	likely benign
REVEL	0.722	pathogenic-leaning
SaProt	LLR -7.09	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 4.5	GERP 0.55, 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 0.00433% European (non-Finnish) · 51/1,178,310 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00373% 60/1,609,498 alleles · very rare exomes 54/1,457,316 · genomes 6/152,182 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00679%	14,734
Finnishnot grpmax-eligible	0.00634%	15,774
European (non-Finnish)grpmax	0.00433%	23,104
Admixed American	0.00168%	59,518
African / African-American	0.00134%	74,870
South Asian	0.00111%	90,262

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1301Cys
Coding: c.3901C>T
MANE Select: NM_015102
dbSNP: rs766610686
Type: single nucleotide variant
Location: chr1:5864433 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 1301: the 'sufficient for basal bodies localization' region

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.Arg1301Leu Uncertain significance ★ ⚠ same residue
NPHP4 p.Arg1301His 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-arg1301cys (accessed [today's date]).

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