Is ANK2 p.Ser2250Leu (c.6749C>T) pathogenic?

ANK2 p.Ser2250Leu (c.6749C>T) is classified Likely pathogenic in ANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-24). AlphaMissense: likely benign (0.2523); Absent from gnomAD v4.1; Associated with Brugada syndrome.

What condition is associated with ANK2 p.Ser2250Leu (c.6749C>T)?

ANK2 p.Ser2250Leu (c.6749C>T) is associated with Brugada syndrome (ClinVar).

How common is ANK2 p.Ser2250Leu (c.6749C>T) in the general population?

ANK2 p.Ser2250Leu (c.6749C>T) 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.Ser2250Leu (c.6749C>T)?

AlphaMissense predicts likely benign (score 0.2523) — an in-silico prediction, not a clinical call.

ANK2 p.Ser2250Leu

c.6749C>T · rs1049367287 · VCV4075802

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2523 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Brugada syndrome

Computational evidence

Protein change
AlphaMissense	0.2523	likely benign ⚠ discordant with ClinVar
REVEL	0.404	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.16 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

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.Ser2250Leu
Coding: c.6749C>T
MANE Select: NM_001148
dbSNP: rs1049367287
Type: single nucleotide variant
Location: chr4:113355367 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2250: the 'disordered' region

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.Ala209Ser Uncertain significance ★★ ⚠ same condition
ANK2 p.Arg321Trp Uncertain significance ★★ same condition
ANK2 p.Arg3942His Uncertain significance ★★ ⚠ 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
ANK2 p.Glu2378Lys Conflicting classifications of pathogenicity ★ ⚠ same condition
ANK2 p.Leu352Ser Uncertain significance ★ ⚠ 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-ser2250leu (accessed [today's date]).

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