Is NPHP4 p.Arg68Trp (c.202C>T) pathogenic?

NPHP4 p.Arg68Trp (c.202C>T) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-08-07). AlphaMissense: likely benign (0.1568); Ultra-rare (popmax 0.0165%, mid); Associated with nephronophthisis 4.

What condition is associated with NPHP4 p.Arg68Trp (c.202C>T)?

NPHP4 p.Arg68Trp (c.202C>T) is associated with nephronophthisis 4, Senior-Loken syndrome 4, nephronophthisis (ClinVar).

How common is NPHP4 p.Arg68Trp (c.202C>T) in the general population?

NPHP4 p.Arg68Trp (c.202C>T) is ultra-rare (popmax 0.0165%, mid) (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.Arg68Trp (c.202C>T)?

AlphaMissense predicts likely benign (score 0.1568) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg68Trp

c.202C>T · rs771873685 · VCV596899

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1568 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

nephronophthisis 4

Computational evidence

Protein change
AlphaMissense	0.1568	likely benign
REVEL	0.53	indeterminate
SaProt	LLR -8.58	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.85 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.1	GERP 1.6, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,074 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00149% 24/1,609,192 alleles · ultra-rare exomes 22/1,457,104 · genomes 2/152,088 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,074
East Asian	0.0067%	14,915
African / African-American	0.00535%	18,695
Admixed American	0.00506%	19,779
Remaining individualsnot grpmax-eligible	0.00321%	31,158
Finnishnot grpmax-eligible	0.00158%	63,170
European (non-Finnish)	0.000849%	117,802

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.Arg68Trp
Coding: c.202C>T
MANE Select: NM_015102
dbSNP: rs771873685
Type: single nucleotide variant
Location: chr1:5978347 (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 p.Arg68Gln Uncertain significance ★★ ⚠ same residue
NPHP4 p.Arg68= Uncertain significance ★ same residue
NPHP4 p.Arg68fs Pathogenic ★ 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

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-arg68trp (accessed [today's date]).

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