Is ANK2 p.Leu352Ser (c.1055T>C) pathogenic?

ANK2 p.Leu352Ser (c.1055T>C) is classified Uncertain significance in ANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-22). AlphaMissense: likely pathogenic (0.9775); Absent from gnomAD v4.1; Associated with Brugada syndrome.

What condition is associated with ANK2 p.Leu352Ser (c.1055T>C)?

ANK2 p.Leu352Ser (c.1055T>C) is associated with Brugada syndrome (ClinVar).

How common is ANK2 p.Leu352Ser (c.1055T>C) in the general population?

ANK2 p.Leu352Ser (c.1055T>C) is absent from gnomAD v4.1 (gnomAD).

How is Brugada syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ANK2 p.Leu352Ser (c.1055T>C)?

AlphaMissense predicts likely pathogenic (score 0.9775) — an in-silico prediction, not a clinical call.

ANK2 p.Leu352Ser

c.1055T>C · VCV3779480

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9775 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

Brugada syndrome

Computational evidence

Protein change
AlphaMissense	0.9775	likely pathogenic
REVEL	0.804	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.5, phastCons 0.99
Regional constraint	o/e 0.77	unconstrained · MANE · 98 kb · p 4.4e-21 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ANK2
Protein: p.Leu352Ser
Coding: c.1055T>C
MANE Select: NM_001148
Type: single nucleotide variant
Location: chr4:113255799 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 352: an α-helix

Full ANK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Brugada syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Brugada syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ANK2 p.Leu352= Likely benign ★★ same residue
ANK2 p.Ala209Ser Uncertain significance ★★ ⚠ same condition
ANK2 p.Arg321Trp Uncertain significance ★★ same condition
ANK2 p.Arg3942His Uncertain significance ★★ ⚠ same condition
ANK2 p.Ser2250Leu Likely pathogenic ★ ⚠ same condition
ANK2 c.11859+1402A>T Uncertain significance ★ same condition
ANK2 c.85-57113C>A Uncertain significance ★ same condition
ANK2 p.Asn687Ser Conflicting classifications of pathogenicity ★ ⚠ 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/ank2-p-leu352ser (accessed [today's date]).

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