Is NPHP4 p.Arg488Gln (c.1463G>A) pathogenic?

NPHP4 p.Arg488Gln (c.1463G>A) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-20). AlphaMissense: likely benign (0.0658); Ultra-rare (popmax 0.0163%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Arg488Gln (c.1463G>A)?

NPHP4 p.Arg488Gln (c.1463G>A) is associated with Inborn genetic diseases, nephronophthisis (ClinVar).

How common is NPHP4 p.Arg488Gln (c.1463G>A) in the general population?

NPHP4 p.Arg488Gln (c.1463G>A) is ultra-rare (popmax 0.0163%, nfe) (gnomAD).

What do computational predictors say about NPHP4 p.Arg488Gln (c.1463G>A)?

AlphaMissense predicts likely benign (score 0.0658) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg488Gln

c.1463G>A · rs375429200 · VCV1021731

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0658 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0163%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0658	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -6.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.1	GERP -3.4
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	0.15	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 0.0163% European (non-Finnish) · 192/1,175,696 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.0128% 206/1,603,952 alleles · ultra-rare exomes 196/1,451,912 · genomes 10/152,040 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0163%	6,123
Remaining individualsnot grpmax-eligible	0.00966%	10,356
Admixed American	0.00682%	14,669
African / African-American	0.00401%	24,909
South Asian	0.00113%	88,516

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.Arg488Gln
Coding: c.1463G>A
MANE Select: NM_015102
dbSNP: rs375429200
Type: single nucleotide variant
Location: chr1:5909192 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis

Similar variants

NPHP4 p.Arg488Gly Uncertain significance ★★ ⚠ same residue
NPHP4 p.Arg488Pro Uncertain significance ★★ ⚠ same residue
NPHP4 p.Arg488Ter 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-arg488gln (accessed [today's date]).

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