Is NECTIN4 p.Arg443Cys (c.1327C>T) pathogenic?

NECTIN4 p.Arg443Cys (c.1327C>T) is classified Conflicting classifications of pathogenicity in NECTIN4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-01). AlphaMissense: likely pathogenic (0.7812); Rare (popmax 0.215%, mid); Associated with ectodermal dysplasia-syndactyly syndrome 1.

What condition is associated with NECTIN4 p.Arg443Cys (c.1327C>T)?

NECTIN4 p.Arg443Cys (c.1327C>T) is associated with ectodermal dysplasia-syndactyly syndrome 1 (ClinVar).

How common is NECTIN4 p.Arg443Cys (c.1327C>T) in the general population?

NECTIN4 p.Arg443Cys (c.1327C>T) is rare (popmax 0.215%, mid) (gnomAD).

What do computational predictors say about NECTIN4 p.Arg443Cys (c.1327C>T)?

AlphaMissense predicts likely pathogenic (score 0.7812) — an in-silico prediction, not a clinical call.

NECTIN4 p.Arg443Cys

c.1327C>T · rs1537044 · VCV418440

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7812 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.215%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ectodermal dysplasia-syndactyly syndrome 1

Computational evidence

Protein change
AlphaMissense	0.7812	likely pathogenic
REVEL	0.178	moderately benign-leaning
SaProt	LLR -7.43	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 4,950 bp · p 0.011 · regional, not allelic
Overall
CADD	32.0	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 0.215% Middle Eastern · 13/6,058 alleles

Filtering AF 0.133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.123%

Overall 0.105% 1,693/1,613,354 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.446%	224
Middle Easterngrpmax	0.215%	466
Remaining individualsnot grpmax-eligible	0.16%	625
Admixed American	0.158%	631
European (non-Finnish)	0.109%	914
South Asian	0.0352%	2,840
African / African-American	0.0333%	3,000
Finnishnot grpmax-eligible	0.00782%	12,790

Ashkenazi Jewish 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: NECTIN4
Protein: p.Arg443Cys
Coding: c.1327C>T
MANE Select: NM_030916
dbSNP: rs1537044
Type: single nucleotide variant
Location: chr1:161072867 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 79.79 · 5 PDB
Residue 443: the 'disordered' region

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.Arg493Pro Uncertain significance ★ ⚠ 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-arg443cys (accessed [today's date]).

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