Is NPHP4 p.Arg488Ter (c.1462C>T) pathogenic?

NPHP4 p.Arg488Ter (c.1462C>T) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-03-19). Very rare (popmax 0.00401%, afr); Associated with Autosomal. recessive NPHP4-related disorders.

What condition is associated with NPHP4 p.Arg488Ter (c.1462C>T)?

NPHP4 p.Arg488Ter (c.1462C>T) is associated with Autosomal. recessive NPHP4-related disorders, nephronophthisis 4, nephronophthisis (ClinVar).

How common is NPHP4 p.Arg488Ter (c.1462C>T) in the general population?

NPHP4 p.Arg488Ter (c.1462C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

NPHP4 p.Arg488Ter

c.1462C>T · rs778043242 · VCV297820

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Conditions

Autosomal. recessive NPHP4-related disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 30
Splicing
SpliceAI	Δ0.25	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 8.5	GERP 1.7, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,750 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.0048% 77/1,604,058 alleles · very rare exomes 64/1,451,934 · genomes 13/152,124 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.122%	816
Remaining individualsnot grpmax-eligible	0.00966%	10,355
African / African-Americangrpmax	0.00401%	24,917
Admixed American	0.00341%	29,348
European (non-Finnish)	0.00238%	41,991
South Asian	0.00226%	44,266

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.Arg488Ter
Coding: c.1462C>T
MANE Select: NM_015102
dbSNP: rs778043242
Type: single nucleotide variant
Location: chr1:5909193 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 488: the 'disordered' region

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

Disease context

Autosomal. recessive NPHP4-related disorders

Also linked: nephronophthisis 4 nephronophthisis

Similar variants

NPHP4 p.Arg488Gly Uncertain significance ★★ ⚠ same residue
NPHP4 p.Arg488Pro Uncertain significance ★★ ⚠ same residue
NPHP4 p.Arg488Gln 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

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-arg488ter (accessed [today's date]).

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