Is ANK2 p.Glu540= (c.1620G>A) pathogenic?

ANK2 p.Glu540= (c.1620G>A) is classified Likely benign in ANK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-01). Very rare (popmax 0.00329%, sas); Associated with Cardiovascular phenotype.

What condition is associated with ANK2 p.Glu540= (c.1620G>A)?

ANK2 p.Glu540= (c.1620G>A) is associated with Cardiovascular phenotype, long QT syndrome (ClinVar).

How common is ANK2 p.Glu540= (c.1620G>A) in the general population?

ANK2 p.Glu540= (c.1620G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

ANK2 p.Glu540=

c.1620G>A · rs536567990 · VCV1776603

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

Cardiovascular phenotype

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 1.3	GERP -4.4, phastCons 1
Overall
CADD	5.673	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,088 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000248% 4/1,614,198 alleles · very rare exomes 3/1,461,880 · genomes 1/152,318 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,363
European (non-Finnish)	8.47e-05%	1,180,036

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.Glu540=
Coding: c.1620G>A
MANE Select: NM_001148
dbSNP: rs536567990
Type: single nucleotide variant
Location: chr4:113274586 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 540: an α-helix

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.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
ANK2 c.2278-3C>T Uncertain significance ★★ same condition
ANK2 c.3125+6G>A 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-glu540 (accessed [today's date]).

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