Is NPHP4 p.Arg735Trp (c.2203C>T) pathogenic?

NPHP4 p.Arg735Trp (c.2203C>T) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2025-12-19). AlphaMissense: likely benign (0.0911); Rare (popmax 0.201%, mid); Associated with Senior-Loken syndrome 4.

What condition is associated with NPHP4 p.Arg735Trp (c.2203C>T)?

NPHP4 p.Arg735Trp (c.2203C>T) is associated with Senior-Loken syndrome 4, nephronophthisis 4, nephronophthisis (ClinVar).

How common is NPHP4 p.Arg735Trp (c.2203C>T) in the general population?

NPHP4 p.Arg735Trp (c.2203C>T) is rare (popmax 0.201%, mid) (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.Arg735Trp (c.2203C>T)?

AlphaMissense predicts likely benign (score 0.0911) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg735Trp

c.2203C>T · rs191913664 · VCV194765

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0911 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.201%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Senior-Loken syndrome 4

Computational evidence

Protein change
AlphaMissense	0.0911	likely benign
REVEL	0.533	indeterminate
SaProt	LLR -8.18	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	25.2	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 0.201% Middle Eastern · 12/5,978 alleles

Filtering AF 0.172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.162%

Overall 0.0343% 545/1,589,512 alleles · rare exomes 412/1,437,240 · genomes 133/152,272 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.201%	498
African / African-American	0.198%	504
Admixed American	0.149%	672
Remaining individualsnot grpmax-eligible	0.0473%	2,113
European (non-Finnish)	0.0222%	4,502
South Asian	0.00783%	12,764
Finnishnot grpmax-eligible	0.00317%	31,586
East Asian	0.00226%	44,166

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.Arg735Trp
Coding: c.2203C>T
MANE Select: NM_015102
dbSNP: rs191913664
Type: single nucleotide variant
Location: chr1:5890969 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 735: a UniProt-annotated variant site (in nphp4)

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 focal segmental glomerulosclerosis

For Senior-Loken syndrome (Orphanet):

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

Similar variants

NPHP4 p.Arg735Gln Uncertain significance ★★ ⚠ same residue
NPHP4 p.Arg735Pro 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

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-arg735trp (accessed [today's date]).

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