Is NPHP4 p.Arg740Cys (c.2218C>T) pathogenic?

NPHP4 p.Arg740Cys (c.2218C>T) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-04). AlphaMissense: likely benign (0.1127); Very rare (popmax 0.00336%, amr); Associated with Senior-Loken syndrome 4.

What condition is associated with NPHP4 p.Arg740Cys (c.2218C>T)?

NPHP4 p.Arg740Cys (c.2218C>T) is associated with Senior-Loken syndrome 4, nephronophthisis 4, nephronophthisis (ClinVar).

How common is NPHP4 p.Arg740Cys (c.2218C>T) in the general population?

NPHP4 p.Arg740Cys (c.2218C>T) is very rare (popmax 0.00336%, amr) (gnomAD).

How is Senior-Loken syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NPHP4 p.Arg740Cys (c.2218C>T)?

AlphaMissense predicts likely benign (score 0.1127) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg740Cys

c.2218C>T · rs766088144 · VCV1018489

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1127 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00336%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Senior-Loken syndrome 4

Computational evidence

Protein change
AlphaMissense	0.1127	likely benign
REVEL	0.3	indeterminate
SaProt	LLR -10.40	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 4.2	GERP 0.075, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	22.5	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 0.00336% Admixed American · 2/59,512 alleles

Filtering AF 0.000557% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000262%

Overall 0.00106% 17/1,603,228 alleles · very rare exomes 15/1,451,032 · genomes 2/152,196 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00336%	29,756
African / African-American	0.00267%	37,386
South Asian	0.00222%	45,014
Remaining individualsnot grpmax-eligible	0.00161%	61,986
Finnishnot grpmax-eligible	0.00158%	63,366
European (non-Finnish)	0.000767%	130,300

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.Arg740Cys
Coding: c.2218C>T
MANE Select: NM_015102
dbSNP: rs766088144
Type: single nucleotide variant
Location: chr1:5890954 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 740: a UniProt-annotated variant site (does not affect interaction with rpgrip1l; does not affect interaction with rpgrip1)

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

Disease context

Senior-Loken syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 4 nephronophthisis

For Senior-Loken syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

NPHP4 p.Arg740Gly Uncertain significance ★ ⚠ same residue
NPHP4 p.Arg740His Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg740cys (accessed [today's date]).

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