Is NECTIN4 p.Pro212Arg (c.635C>G) pathogenic?

NECTIN4 p.Pro212Arg (c.635C>G) is classified Pathogenic in NECTIN4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2011-05-01). AlphaMissense: likely pathogenic (0.99); Very rare (popmax 0.0011%, sas); Associated with ectodermal dysplasia-syndactyly syndrome 1.

What condition is associated with NECTIN4 p.Pro212Arg (c.635C>G)?

NECTIN4 p.Pro212Arg (c.635C>G) is associated with ectodermal dysplasia-syndactyly syndrome 1 (ClinVar).

How common is NECTIN4 p.Pro212Arg (c.635C>G) in the general population?

NECTIN4 p.Pro212Arg (c.635C>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about NECTIN4 p.Pro212Arg (c.635C>G)?

AlphaMissense predicts likely pathogenic (score 0.99) — an in-silico prediction, not a clinical call.

NECTIN4 p.Pro212Arg

c.635C>G · rs387907014 · VCV30794

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.99 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ectodermal dysplasia-syndactyly syndrome 1

Computational evidence

Protein change
AlphaMissense	0.99	likely pathogenic ✓ concordant with ClinVar · top 3% in NECTIN4
REVEL	0.784	moderately pathogenic-leaning
SaProt	LLR -17.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 4,950 bp · p 0.011 · regional, not allelic
Overall
CADD	29.8	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 0.0011% South Asian · 1/91,082 alleles

Overall 0.000657% 1/152,196 alleles · very rare

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.Pro212Arg
Coding: c.635C>G
MANE Select: NM_030916
dbSNP: rs387907014
Type: single nucleotide variant
Location: chr1:161077548 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 79.79 · 5 PDB
Residue 212: a disulfide bond; the ig-like c2-type 1 domain

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.Arg493Pro Uncertain significance ★ ⚠ same condition
NECTIN4 p.Tyr125Ser 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/nectin4-p-pro212arg (accessed [today's date]).

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