Is NPHP3 p.Glu380Val (c.1139A>T) pathogenic?

NPHP3 p.Glu380Val (c.1139A>T) is classified Uncertain significance in NPHP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-05). AlphaMissense: likely benign (0.3222); Very rare (popmax 0.0011%, nfe); Associated with renal-hepatic-pancreatic dysplasia 1.

What condition is associated with NPHP3 p.Glu380Val (c.1139A>T)?

NPHP3 p.Glu380Val (c.1139A>T) is associated with renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome, nephronophthisis 3 (ClinVar).

How common is NPHP3 p.Glu380Val (c.1139A>T) in the general population?

NPHP3 p.Glu380Val (c.1139A>T) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about NPHP3 p.Glu380Val (c.1139A>T)?

AlphaMissense predicts likely benign (score 0.3222) — an in-silico prediction, not a clinical call.

NPHP3 p.Glu380Val

c.1139A>T · rs368626865 · VCV1919161

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3222 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

renal-hepatic-pancreatic dysplasia 1

Computational evidence

Protein change
AlphaMissense	0.3222	likely benign
REVEL	0.695	pathogenic-leaning
SaProt	LLR -8.80	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.48	acceptor loss · deltas
Pangolin	Δ0.27	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.8	GERP 2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	22.7	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 0.0011% European (non-Finnish) · 13/1,180,020 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000805% 13/1,614,166 alleles · very rare exomes 13/1,461,816 · genomes 0/152,350 · joint denominator

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.Glu380Val
Coding: c.1139A>T
MANE Select: NM_153240
dbSNP: rs368626865
Type: single nucleotide variant
Location: chr3:132708237 (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

renal-hepatic-pancreatic dysplasia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: NPHP3-related Meckel-like syndrome nephronophthisis 3 nephronophthisis

Similar variants

NPHP3 p.Glu380Lys Uncertain significance ★ ⚠ 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-glu380val (accessed [today's date]).

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