Is NPHP4 p.Arg390His (c.1169G>A) pathogenic?

NPHP4 p.Arg390His (c.1169G>A) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-02-19). AlphaMissense: likely pathogenic (0.5746); Rare (popmax 0.111%, eas); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Arg390His (c.1169G>A)?

NPHP4 p.Arg390His (c.1169G>A) is associated with Inborn genetic diseases, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Arg390His (c.1169G>A) in the general population?

NPHP4 p.Arg390His (c.1169G>A) is rare (popmax 0.111%, eas) (gnomAD).

What do computational predictors say about NPHP4 p.Arg390His (c.1169G>A)?

AlphaMissense predicts likely pathogenic (score 0.5746) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg390His

c.1169G>A · rs146637048 · VCV1022837

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5746 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.111%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5746	likely pathogenic
REVEL	0.578	indeterminate
SaProt	LLR -8.25	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	26.7	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 0.111% East Asian · 50/44,872 alleles

Filtering AF 0.0867% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0781%

Overall 0.0044% 71/1,613,630 alleles · rare exomes 62/1,461,348 · genomes 9/152,282 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.111%	897
Middle Eastern	0.0168%	5,970
African / African-American	0.00666%	15,007
European (non-Finnish)	0.00119%	84,273
South Asian	0.0011%	91,080

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.Arg390His
Coding: c.1169G>A
MANE Select: NM_015102
dbSNP: rs146637048
Type: single nucleotide variant
Location: chr1:5933280 (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

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

Also linked: nephronophthisis 4 Senior-Loken syndrome 4 nephronophthisis

Similar variants

NPHP4 p.Arg390Cys Uncertain significance ★★ ⚠ same residue
NPHP4 p.Arg390= Likely benign ★ same residue
NPHP4 p.Arg390Leu 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

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-arg390his (accessed [today's date]).

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