Is NPHP4 p.Arg316Cys (c.946C>T) pathogenic?

NPHP4 p.Arg316Cys (c.946C>T) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-10-07). AlphaMissense: likely benign (0.167); Ultra-rare (popmax 0.0783%, amr); Associated with nephronophthisis 4.

What condition is associated with NPHP4 p.Arg316Cys (c.946C>T)?

NPHP4 p.Arg316Cys (c.946C>T) is associated with nephronophthisis 4, Senior-Loken syndrome 4, nephronophthisis (ClinVar).

How common is NPHP4 p.Arg316Cys (c.946C>T) in the general population?

NPHP4 p.Arg316Cys (c.946C>T) is ultra-rare (popmax 0.0783%, 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.Arg316Cys (c.946C>T)?

AlphaMissense predicts likely benign (score 0.167) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg316Cys

c.946C>T · rs761345213 · VCV531618

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.167 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0783%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

nephronophthisis 4

Computational evidence

Protein change
AlphaMissense	0.167	likely benign
REVEL	0.457	indeterminate
SaProt	LLR -10.05	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	28.1	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 0.0783% Admixed American · 47/60,026 alleles

Filtering AF 0.0604% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0542%

Overall 0.00973% 157/1,613,880 alleles · ultra-rare exomes 147/1,461,584 · genomes 10/152,296 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0783%	1,277
East Asian	0.0379%	2,640
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,921
Remaining individualsnot grpmax-eligible	0.0112%	8,926
European (non-Finnish)	0.00678%	14,748
South Asian	0.0011%	91,074

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.Arg316Cys
Coding: c.946C>T
MANE Select: NM_015102
dbSNP: rs761345213
Type: single nucleotide variant
Location: chr1:5948116 (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

nephronophthisis 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Senior-Loken syndrome 4 nephronophthisis

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

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
NPHP4 c.992+2T>C 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-arg316cys (accessed [today's date]).

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