Is NPHP3 p.Glu381Lys (c.1141G>A) pathogenic?

NPHP3 p.Glu381Lys (c.1141G>A) is classified Uncertain significance in NPHP3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-06-26). AlphaMissense: likely benign (0.3372); Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with NPHP3 p.Glu381Lys (c.1141G>A)?

NPHP3 p.Glu381Lys (c.1141G>A) is associated with Inborn genetic diseases, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Glu381Lys (c.1141G>A) in the general population?

NPHP3 p.Glu381Lys (c.1141G>A) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about NPHP3 p.Glu381Lys (c.1141G>A)?

AlphaMissense predicts likely benign (score 0.3372) — an in-silico prediction, not a clinical call.

NPHP3 p.Glu381Lys

c.1141G>A · rs748615630 · VCV598507

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.3372 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

⚠ 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	0.3372	likely benign
REVEL	0.52	indeterminate
SaProt	LLR -7.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Pangolin	Δ0.24	loss · gain 0.02 · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.87 · regional, not allelic
Overall
CADD	23.3	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 0.0107% African / African-American · 8/74,942 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000991% 16/1,614,022 alleles · ultra-rare exomes 13/1,461,802 · genomes 3/152,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,368
Remaining individualsnot grpmax-eligible	0.0064%	15,622
Admixed American	0.00333%	30,003
East Asian	0.00223%	44,898
European (non-Finnish)	8.47e-05%	1,180,016

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.Glu381Lys
Coding: c.1141G>A
MANE Select: NM_153240
dbSNP: rs748615630
Type: single nucleotide variant
Location: chr3:132708235 (GRCh38)

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

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-glu381lys (accessed [today's date]).

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