Is ANK2 p.Arg506His (c.1517G>A) pathogenic?

ANK2 p.Arg506His (c.1517G>A) is classified Uncertain significance in ANK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-23). AlphaMissense: likely pathogenic (0.959); Very rare (popmax 0.00446%, eas); Associated with long QT syndrome.

What condition is associated with ANK2 p.Arg506His (c.1517G>A)?

ANK2 p.Arg506His (c.1517G>A) is associated with long QT syndrome (ClinVar).

How common is ANK2 p.Arg506His (c.1517G>A) in the general population?

ANK2 p.Arg506His (c.1517G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about ANK2 p.Arg506His (c.1517G>A)?

AlphaMissense predicts likely pathogenic (score 0.959) — an in-silico prediction, not a clinical call.

ANK2 p.Arg506His

c.1517G>A · rs760370075 · VCV1017225

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.959 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

long QT syndrome

Computational evidence

Protein change
AlphaMissense	0.959	likely pathogenic
REVEL	0.611	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 98 kb · p 4.4e-21 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.00446% East Asian · 2/44,884 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000805% 13/1,613,982 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,442
South Asian	0.0011%	91,072
European (non-Finnish)	0.000847%	118,002

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.Arg506His
Coding: c.1517G>A
MANE Select: NM_001148
dbSNP: rs760370075
Type: single nucleotide variant
Location: chr4:113274483 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 506: an α-helix

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

Disease context

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

Similar variants

ANK2 p.Arg3113Ter 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
ANK2 c.693+6G>A Uncertain significance ★★ same condition
ANK2 c.85-3C>T 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-arg506his (accessed [today's date]).

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