Is NECTIN1 p.Pro342Ser (c.1024C>T) pathogenic?

NECTIN1 p.Pro342Ser (c.1024C>T) is classified Uncertain significance in NECTIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-08). AlphaMissense: likely benign (0.0755); Ultra-rare (popmax 0.0251%, amr).

How common is NECTIN1 p.Pro342Ser (c.1024C>T) in the general population?

NECTIN1 p.Pro342Ser (c.1024C>T) is ultra-rare (popmax 0.0251%, amr) (gnomAD).

What do computational predictors say about NECTIN1 p.Pro342Ser (c.1024C>T)?

AlphaMissense predicts likely benign (score 0.0755) — an in-silico prediction, not a clinical call.

NECTIN1 p.Pro342Ser

c.1024C>T · rs762583153 · VCV2067593

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0755 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0251%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0755	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 64 kb · p 8.1e-06 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0251% Admixed American · 15/59,696 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0125%

Overall 0.001% 16/1,593,930 alleles · ultra-rare exomes 15/1,441,764 · genomes 1/152,166 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0251%	3,980
European (non-Finnish)	8.51e-05%	1,175,646

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: NECTIN1
Protein: p.Pro342Ser
Coding: c.1024C>T
MANE Select: NM_002855
dbSNP: rs762583153
Type: single nucleotide variant
Location: chr11:119665277 (GRCh38)
Gene constraint: LOEUF 0.659 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.80 · 6 PDB
Residue 342: a UniProt-annotated variant site (in edmi); a UniProt-annotated variant site (in edmi and ofc7)

Full NECTIN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NECTIN1 c.*1139G>A Uncertain significance ★★ same type
NECTIN1 c.*1179C>G Uncertain significance ★★ same type
NECTIN1 c.*1595C>A Uncertain significance ★★ same type
NECTIN1 c.*185T>C Uncertain significance ★★ same type
NECTIN1 c.*2416A>G Uncertain significance ★★ same type
NECTIN1 c.*3440G>A Uncertain significance ★★ same type
NECTIN1 c.*3705G>A Uncertain significance ★★ same type
NECTIN1 c.*607C>A Uncertain significance ★★ 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/nectin1-p-pro342ser (accessed [today's date]).

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