Is ANK2 p.Ala1819= (c.5457G>A) pathogenic?

ANK2 p.Ala1819= (c.5457G>A) is classified Likely benign in ANK2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-27). Ultra-rare (popmax 0.0493%, afr); Associated with Cardiovascular phenotype.

What condition is associated with ANK2 p.Ala1819= (c.5457G>A)?

ANK2 p.Ala1819= (c.5457G>A) is associated with Cardiovascular phenotype, long QT syndrome (ClinVar).

How common is ANK2 p.Ala1819= (c.5457G>A) in the general population?

ANK2 p.Ala1819= (c.5457G>A) is ultra-rare (popmax 0.0493%, afr) (gnomAD).

ANK2 p.Ala1819=

c.5457G>A · rs138113206 · VCV457042

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -3.6
Overall
CADD	1.02	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% African / African-American · 37/75,014 alleles

Filtering AF 0.0368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0323%

Overall 0.00421% 68/1,613,988 alleles · ultra-rare exomes 44/1,461,784 · genomes 24/152,204 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0493%	2,027
Admixed American	0.0283%	3,530
Middle Eastern	0.0165%	6,058
East Asian	0.00669%	14,955
Remaining individualsnot grpmax-eligible	0.0064%	15,626
South Asian	0.00329%	30,355
European (non-Finnish)	0.000254%	393,323

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: ANK2
Protein: p.Ala1819=
Coding: c.5457G>A
MANE Select: NM_001148
dbSNP: rs138113206
Type: single nucleotide variant
Location: chr4:113354075 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1819: the 'disordered' region; the 'repeat-rich region' region

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: long QT syndrome

Similar variants

ANK2 p.Ala1819Thr Uncertain significance ★ ⚠ same residue
ANK2 p.Ala1819Val Conflicting classifications of pathogenicity ★ ⚠ same residue
ANK2 p.Arg3113Ter Pathogenic ★★ same condition
ANK2 p.Arg895Ter Pathogenic/Likely pathogenic ★★ same condition
ANK2 p.Arg977Ter Pathogenic ★★ same condition
ANK2 c.11611-3T>A Uncertain significance ★★ same condition
ANK2 c.1783-3C>T Uncertain significance ★★ same condition
ANK2 c.2079+5T>G 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-ala1819 (accessed [today's date]).

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