Is NPHP3 p.Arg397His (c.1190G>A) pathogenic?

NPHP3 p.Arg397His (c.1190G>A) is classified Conflicting classifications of pathogenicity in NPHP3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-24). AlphaMissense: likely benign (0.0847); Ultra-rare (popmax 0.0571%, sas); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Arg397His (c.1190G>A)?

NPHP3 p.Arg397His (c.1190G>A) is associated with nephronophthisis, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Arg397His (c.1190G>A) in the general population?

NPHP3 p.Arg397His (c.1190G>A) is ultra-rare (popmax 0.0571%, 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 NPHP3 p.Arg397His (c.1190G>A)?

AlphaMissense predicts likely benign (score 0.0847) — an in-silico prediction, not a clinical call.

NPHP3 p.Arg397His

c.1190G>A · rs755094682 · VCV839634

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0847 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0571%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.0847	likely benign
REVEL	0.523	indeterminate
SaProt	LLR -8.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.38	GERP 0.27, phastCons 0.024
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	21.2	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 0.0571% South Asian · 52/91,078 alleles

Filtering AF 0.0447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0403%

Overall 0.00644% 104/1,613,680 alleles · ultra-rare exomes 101/1,461,456 · genomes 3/152,224 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0571%	1,752
Remaining individualsnot grpmax-eligible	0.0048%	20,824
European (non-Finnish)	0.00407%	24,576
Admixed American	0.00167%	60,008

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: NPHP3
Protein: p.Arg397His
Coding: c.1190G>A
MANE Select: NM_153240
dbSNP: rs755094682
Type: single nucleotide variant
Location: chr3:132708186 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.59 · 1 PDB
Residue 397: a UniProt-annotated variant site (in nphp3)

Full NPHP3 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: renal-hepatic-pancreatic dysplasia 1 NPHP3-related Meckel-like syndrome nephronophthisis 3

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP3 p.Arg397Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
NPHP3 c.1985+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP3 c.3201+1G>T Likely pathogenic ★★ same condition
NPHP3 c.393+1G>C Likely pathogenic ★★ same condition
NPHP3 c.520-1G>T Pathogenic ★★ same condition
NPHP3 c.823+1G>T Likely pathogenic ★★ same condition
NPHP3 c.958-2A>G Pathogenic ★★ same condition
NPHP3 p.Arg1125Ter 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/nphp3-p-arg397his (accessed [today's date]).

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