Is NECTIN2 p.Pro53= (c.159G>A) pathogenic?

NECTIN2 p.Pro53= (c.159G>A) is classified Likely benign in NECTIN2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-05-02). Rare (popmax 0.561%, mid); Associated with NECTIN2-related disorder.

What condition is associated with NECTIN2 p.Pro53= (c.159G>A)?

NECTIN2 p.Pro53= (c.159G>A) is associated with NECTIN2-related disorder (ClinVar).

How common is NECTIN2 p.Pro53= (c.159G>A) in the general population?

NECTIN2 p.Pro53= (c.159G>A) is rare (popmax 0.561%, mid) (gnomAD).

NECTIN2 p.Pro53=

c.159G>A · rs113179384 · VCV3044075

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.561%, mid)

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 -6.5	GERP -3.7
Overall
CADD	2.064	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.561% Middle Eastern · 34/6,060 alleles

Filtering AF 0.413% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.362%

Overall 0.0281% 454/1,614,100 alleles · rare exomes 424/1,461,846 · genomes 30/152,254 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.561%	178
Remaining individualsnot grpmax-eligible	0.0432%	2,315
European (non-Finnish)	0.0303%	3,305
Admixed American	0.0283%	3,530
East Asian	0.0156%	6,409
African / African-American	0.0147%	6,820
Finnishnot grpmax-eligible	0.00156%	64,012

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.Pro53=
Coding: c.159G>A
MANE Select: NM_001042724
dbSNP: rs113179384
Type: single nucleotide variant
Location: chr19:44865341 (GRCh38)
Gene constraint: LOEUF 0.658 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.78 · 8 PDB
Residue 53: the ig-like v-type domain

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-pro53 (accessed [today's date]).

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