Is NPHP3 p.Val415Phe (c.1243G>T) pathogenic?

NPHP3 p.Val415Phe (c.1243G>T) is classified Uncertain significance in NPHP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-09). AlphaMissense: likely benign (0.217); Ultra-rare (popmax 0.034%, sas); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Val415Phe (c.1243G>T)?

NPHP3 p.Val415Phe (c.1243G>T) is associated with nephronophthisis (ClinVar).

How common is NPHP3 p.Val415Phe (c.1243G>T) in the general population?

NPHP3 p.Val415Phe (c.1243G>T) is ultra-rare (popmax 0.034%, 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.Val415Phe (c.1243G>T)?

AlphaMissense predicts likely benign (score 0.217) — an in-silico prediction, not a clinical call.

NPHP3 p.Val415Phe

c.1243G>T · rs538529082 · VCV2177290

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.217 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.034%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.217	likely benign
REVEL	0.576	indeterminate
SaProt	LLR -6.73	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.20	donor loss, 32 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 2.2	GERP 0.29, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.034% South Asian · 31/91,090 alleles

Filtering AF 0.0246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00254% 41/1,614,194 alleles · ultra-rare exomes 36/1,461,860 · genomes 5/152,334 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.034%	2,938
Remaining individualsnot grpmax-eligible	0.0128%	7,813
European (non-Finnish)	0.000169%	590,019

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.Val415Phe
Coding: c.1243G>T
MANE Select: NM_153240
dbSNP: rs538529082
Type: single nucleotide variant
Location: chr3:132708133 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.59 · 1 PDB

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

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP3 p.Val415= Likely benign ★★ 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.958-2A>G Pathogenic ★★ same condition
NPHP3 p.Arg1125Ter Pathogenic ★★ same condition
NPHP3 p.Arg1259Ter Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Arg142Ter 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/nphp3-p-val415phe (accessed [today's date]).

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