Is NECTIN2 p.Arg43Ter (c.127C>T) pathogenic?

NECTIN2 p.Arg43Ter (c.127C>T) is classified Uncertain significance in NECTIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-10). Very rare (popmax 8.48e-05%, nfe); Associated with cerebral palsy.

What condition is associated with NECTIN2 p.Arg43Ter (c.127C>T)?

NECTIN2 p.Arg43Ter (c.127C>T) is associated with cerebral palsy (ClinVar).

How common is NECTIN2 p.Arg43Ter (c.127C>T) in the general population?

NECTIN2 p.Arg43Ter (c.127C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

NECTIN2 p.Arg43Ter

c.127C>T · rs1365743374 · VCV1172826

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

cerebral palsy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 9
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.6	GERP 1.7, phastCons 0.002
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,736 alleles

Overall 6.2e-05% 1/1,613,562 alleles · very rare exomes 1/1,461,342 · genomes 0/152,220 · joint denominator

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: NECTIN2
Protein: p.Arg43Ter
Coding: c.127C>T
MANE Select: NM_001042724
dbSNP: rs1365743374
Type: single nucleotide variant
Location: chr19:44865309 (GRCh38)
Gene constraint: LOEUF 0.658 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.78 · 8 PDB
Residue 43: a β-strand; the ig-like v-type domain

Full NECTIN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cerebral palsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NECTIN2 p.Arg286His Benign ★★ same type
NECTIN2 p.Asp122= Benign ★★ same type
NECTIN2 p.Glu401Gln Benign ★★ same type
NECTIN2 p.Gly47Arg Uncertain significance ★ ⚠ same type
NECTIN2 p.Thr472Ile Uncertain significance ★ ⚠ same type
NECTIN2 p.Tyr454Cys Uncertain significance ★ ⚠ same type
NECTIN2 p.Val42Met Uncertain significance ★ same type
NECTIN2 c.1042+3795G>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/nectin2-p-arg43ter (accessed [today's date]).

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