Is NEDD4L p.Pro482= (c.1446A>G) pathogenic?

NEDD4L p.Pro482= (c.1446A>G) is classified Likely benign in NEDD4L (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-08). Very rare (popmax 0.00127%, nfe); Associated with periventricular nodular heterotopia 7.

What condition is associated with NEDD4L p.Pro482= (c.1446A>G)?

NEDD4L p.Pro482= (c.1446A>G) is associated with periventricular nodular heterotopia 7 (ClinVar).

How common is NEDD4L p.Pro482= (c.1446A>G) in the general population?

NEDD4L p.Pro482= (c.1446A>G) is very rare (popmax 0.00127%, nfe) (gnomAD).

NEDD4L p.Pro482=

c.1446A>G · rs773408353 · VCV1674177

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Conditions

periventricular nodular heterotopia 7

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.67	GERP -5.9
Overall
CADD	7.513	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00127% European (non-Finnish) · 15/1,179,866 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00105% 17/1,613,938 alleles · very rare exomes 17/1,461,630 · genomes 0/152,308 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)grpmax	0.00127%	78,658

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: NEDD4L
Protein: p.Pro482=
Coding: c.1446A>G
MANE Select: NM_001144967
dbSNP: rs773408353
Type: single nucleotide variant
Location: chr18:58342974 (GRCh38)
Gene constraint: LOEUF 0.457 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.76 · 20 PDB
Residue 482: the 'disordered' region

Full NEDD4L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

periventricular nodular heterotopia 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NEDD4L p.Arg208Gln Pathogenic/Likely pathogenic ★★ same condition
NEDD4L p.Glu893Lys Pathogenic/Likely pathogenic ★★ same condition
NEDD4L p.Met749Val Likely pathogenic ★★ same condition
NEDD4L p.Ala508Val Uncertain significance ★★ ⚠ same condition
NEDD4L p.Arg252Cys Uncertain significance ★★ ⚠ same condition
NEDD4L p.Arg512Gln Uncertain significance ★★ ⚠ same condition
NEDD4L p.Arg958Gln Uncertain significance ★★ ⚠ same condition
NEDD4L p.Asn213Ser Uncertain significance ★★ ⚠ 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/nedd4l-p-pro482 (accessed [today's date]).

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