Is NEDD4 p.Pro668Arg (c.2003C>G) pathogenic?

NEDD4 p.Pro668Arg (c.2003C>G) is classified Uncertain significance in NEDD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-28). AlphaMissense: likely benign (0.2058); Absent from gnomAD v4.1.

How common is NEDD4 p.Pro668Arg (c.2003C>G) in the general population?

NEDD4 p.Pro668Arg (c.2003C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NEDD4 p.Pro668Arg (c.2003C>G)?

AlphaMissense predicts likely benign (score 0.2058) — an in-silico prediction, not a clinical call.

NEDD4 p.Pro668Arg

c.2003C>G · rs2542973502 · VCV2340025

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2058 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2058	likely benign
REVEL	0.294	indeterminate
SaProt	LLR -9.74	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 164 kb · p 0.013 · regional, not allelic
Overall
CADD	26.6	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1087R vs ClinVar P668R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NEDD4
Protein: p.Pro668Arg
Coding: c.2003C>G
MANE Select: NM_006154
dbSNP: rs2542973502
Type: single nucleotide variant
Location: chr15:55840475 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.86 · 15 PDB
Residue 1087 UniProt numbering: the hect domain; an α-helix

Full NEDD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NEDD4 p.Arg548His Uncertain significance ★★ ⚠ same type
NEDD4 c.1484-6C>T Likely benign ★★ same type
NEDD4 c.291+7901C>A Benign/Likely benign ★★ same type
NEDD4 c.291+7911A>G Benign ★★ same type
NEDD4 c.291+8022G>C Likely benign ★★ same type
NEDD4 c.291+8368T>A Benign/Likely benign ★★ same type
NEDD4 c.291+8666G>A Benign ★★ same type
NEDD4 c.291+8732T>A Benign ★★ same type

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/nedd4-p-pro668arg (accessed [today's date]).

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