Is ANK2 p.Arg3263Ser (c.9789G>T) pathogenic?

ANK2 p.Arg3263Ser (c.9789G>T) is classified Conflicting classifications of pathogenicity in ANK2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-25). AlphaMissense: ambiguous (0.3882); Ultra-rare (popmax 0.0164%, mid); Associated with long QT syndrome.

What condition is associated with ANK2 p.Arg3263Ser (c.9789G>T)?

ANK2 p.Arg3263Ser (c.9789G>T) is associated with long QT syndrome (ClinVar).

How common is ANK2 p.Arg3263Ser (c.9789G>T) in the general population?

ANK2 p.Arg3263Ser (c.9789G>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ANK2 p.Arg3263Ser (c.9789G>T)?

AlphaMissense predicts ambiguous (score 0.3882) — an in-silico prediction, not a clinical call.

ANK2 p.Arg3263Ser

c.9789G>T · rs765175059 · VCV2731568

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3882 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

long QT syndrome

Computational evidence

Protein change
AlphaMissense	0.3882	ambiguous
REVEL	0.597	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.76, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.16 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00173% 28/1,613,908 alleles · ultra-rare exomes 26/1,461,788 · genomes 2/152,120 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
European (non-Finnish)	0.00203%	49,166
Admixed American	0.00167%	59,990
Remaining individualsnot grpmax-eligible	0.0016%	62,484
South Asian	0.0011%	91,080

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.Arg3263Ser
Coding: c.9789G>T
MANE Select: NM_001148
dbSNP: rs765175059
Type: single nucleotide variant
Location: chr4:113358407 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 3263: the 'disordered' region

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.Arg3263Thr Uncertain significance ★ ⚠ same residue
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

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-arg3263ser (accessed [today's date]).

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