Is NECTIN2 p.Phe440= (c.1320T>C) pathogenic?

NECTIN2 p.Phe440= (c.1320T>C) is classified Likely benign in NECTIN2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-08-18). Rare (popmax 0.276%, nfe); Associated with NECTIN2-related disorder.

What condition is associated with NECTIN2 p.Phe440= (c.1320T>C)?

NECTIN2 p.Phe440= (c.1320T>C) is associated with NECTIN2-related disorder (ClinVar).

How common is NECTIN2 p.Phe440= (c.1320T>C) in the general population?

NECTIN2 p.Phe440= (c.1320T>C) is rare (popmax 0.276%, nfe) (gnomAD).

NECTIN2 p.Phe440=

c.1320T>C · rs182813625 · VCV3043121

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.276%, nfe)

Conditions

NECTIN2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.2	GERP -3.1
Overall
CADD	2.429	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.276% European (non-Finnish) · 3,262/1,179,756 alleles

Filtering AF 0.269% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.265%

Overall 0.22% 3,550/1,612,406 alleles · rare exomes 3,307/1,460,136 · genomes 243/152,270 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.276%	362
Admixed American	0.182%	551
Remaining individualsnot grpmax-eligible	0.173%	577
African / African-American	0.06%	1,666
Finnishnot grpmax-eligible	0.0266%	3,766
Middle Eastern	0.0206%	4,848
South Asian	0.00879%	11,376

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.Phe440=
Coding: c.1320T>C
MANE Select: NM_001042724
dbSNP: rs182813625
Type: single nucleotide variant
Location: chr19:44886192 (GRCh38)
Gene constraint: LOEUF 0.658 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.78 · 8 PDB

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

Disease context

NECTIN2-related disorder

Similar variants

NECTIN2 p.Tyr454Cys Uncertain significance ★ ⚠ same condition
NECTIN2 p.Thr390Met Uncertain significance ⚠ same condition
NECTIN2 c.1042+3797G>T Likely benign same condition
NECTIN2 c.1043-3861G>A Likely benign same condition
NECTIN2 c.1261-9C>T Benign same condition
NECTIN2 c.89-10C>T Likely benign same condition
NECTIN2 p.Ala214= Likely benign same condition
NECTIN2 p.Arg222Cys Likely benign ⚠ 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/nectin2-p-phe440 (accessed [today's date]).

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