Is NPHP3 p.Arg39Leu (c.116G>T) pathogenic?

NPHP3 p.Arg39Leu (c.116G>T) is classified Uncertain significance in NPHP3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-04). AlphaMissense: likely pathogenic (0.6055); Ultra-rare (popmax 0.0201%, eas); Associated with nephronophthisis 3.

What condition is associated with NPHP3 p.Arg39Leu (c.116G>T)?

NPHP3 p.Arg39Leu (c.116G>T) is associated with nephronophthisis 3, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Arg39Leu (c.116G>T) in the general population?

NPHP3 p.Arg39Leu (c.116G>T) is ultra-rare (popmax 0.0201%, eas) (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.Arg39Leu (c.116G>T)?

AlphaMissense predicts likely pathogenic (score 0.6055) — an in-silico prediction, not a clinical call.

NPHP3 p.Arg39Leu

c.116G>T · rs753467164 · VCV999142

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6055 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

nephronophthisis 3

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.6055	likely pathogenic
REVEL	0.612	indeterminate
SaProt	LLR -6.55	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4.3	GERP 0.47, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	24.3	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 0.0201% East Asian · 8/39,874 alleles

Filtering AF 0.00989% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0072%

Overall 0.000577% 9/1,559,376 alleles · ultra-rare exomes 7/1,407,418 · genomes 2/151,958 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,984
European (non-Finnish)	8.6e-05%	1,162,939

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.Arg39Leu
Coding: c.116G>T
MANE Select: NM_153240
dbSNP: rs753467164
Type: single nucleotide variant
Location: chr3:132722240 (GRCh38)

Full NPHP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephronophthisis 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: renal-hepatic-pancreatic dysplasia 1 NPHP3-related Meckel-like syndrome nephronophthisis

For Nephronophthisis (Orphanet):

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

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-arg39leu (accessed [today's date]).

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