Is NPHP4 p.Pro497Arg (c.1490C>G) pathogenic?

NPHP4 p.Pro497Arg (c.1490C>G) is classified Benign in NPHP4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1765); Low-frequency (popmax 4.29%, sas); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Pro497Arg (c.1490C>G)?

NPHP4 p.Pro497Arg (c.1490C>G) is associated with nephronophthisis, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Pro497Arg (c.1490C>G) in the general population?

NPHP4 p.Pro497Arg (c.1490C>G) is low-frequency (popmax 4.29%, sas) (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.Pro497Arg (c.1490C>G)?

AlphaMissense predicts likely benign (score 0.1765) — an in-silico prediction, not a clinical call.

NPHP4 p.Pro497Arg

c.1490C>G · rs375051705 · VCV215518

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1765 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.29%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.1765	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -7.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	25.0	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 4.29% South Asian · 3,778/88,078 alleles

Filtering AF 4.18% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.13%

Overall 0.25% 3,997/1,601,166 alleles · low-frequency exomes 3,785/1,448,842 · genomes 212/152,324 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	4.29%	23
Remaining individualsnot grpmax-eligible	0.232%	431
Middle Eastern	0.182%	550
Ashkenazi Jewishnot grpmax-eligible	0.0307%	3,259
African / African-American	0.012%	8,318
Admixed American	0.00687%	14,562
East Asian	0.0045%	22,221
European (non-Finnish)	0.00324%	30,898
Finnishnot grpmax-eligible	0.00317%	31,554

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.Pro497Arg
Coding: c.1490C>G
MANE Select: NM_015102
dbSNP: rs375051705
Type: single nucleotide variant
Location: chr1:5909165 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 497: the 'disordered' region

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

Disease context

nephronophthisis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 4 Senior-Loken syndrome 4

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

NPHP4 p.Pro497Thr 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
NPHP4 c.518-2A>G 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-pro497arg (accessed [today's date]).

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