Is NECTIN4 p.Arg493Pro (c.1478G>C) pathogenic?

NECTIN4 p.Arg493Pro (c.1478G>C) is classified Uncertain significance in NECTIN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-03). AlphaMissense: likely pathogenic (0.9431); Absent from gnomAD v4.1; Associated with ectodermal dysplasia-syndactyly syndrome 1.

What condition is associated with NECTIN4 p.Arg493Pro (c.1478G>C)?

NECTIN4 p.Arg493Pro (c.1478G>C) is associated with ectodermal dysplasia-syndactyly syndrome 1 (ClinVar).

How common is NECTIN4 p.Arg493Pro (c.1478G>C) in the general population?

NECTIN4 p.Arg493Pro (c.1478G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NECTIN4 p.Arg493Pro (c.1478G>C)?

AlphaMissense predicts likely pathogenic (score 0.9431) — an in-silico prediction, not a clinical call.

NECTIN4 p.Arg493Pro

c.1478G>C · rs753298397 · VCV1029983

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9431 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ectodermal dysplasia-syndactyly syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9431	likely pathogenic · top 8% in NECTIN4
REVEL	0.223	benign-leaning
SaProt	LLR -14.79	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 4,950 bp · p 0.011 · regional, not allelic
Overall
CADD	29.1	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

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: NECTIN4
Protein: p.Arg493Pro
Coding: c.1478G>C
MANE Select: NM_030916
dbSNP: rs753298397
Type: single nucleotide variant
Location: chr1:161072716 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 79.79 · 5 PDB

Full NECTIN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ectodermal dysplasia-syndactyly syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NECTIN4 p.Pro463Ala Uncertain significance ★★ ⚠ same condition
NECTIN4 p.Thr497Met Uncertain significance ★★ ⚠ same condition
NECTIN4 p.Arg294Ter Pathogenic ★ same condition
NECTIN4 p.Arg506Trp Likely pathogenic ★ ⚠ same condition
NECTIN4 p.Gln77Ter Pathogenic ★ same condition
NECTIN4 p.Arg443Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
NECTIN4 p.Tyr125Ser Uncertain significance ★ ⚠ same condition
NECTIN4 p.Arg284Gln 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/nectin4-p-arg493pro (accessed [today's date]).

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