Is ANK2 p.Arg3642Gln (c.10925G>A) pathogenic?

ANK2 p.Arg3642Gln (c.10925G>A) is classified Uncertain significance in ANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-14). AlphaMissense: likely pathogenic (0.978); Ultra-rare (popmax 0.0164%, mid); Associated with long QT syndrome.

What condition is associated with ANK2 p.Arg3642Gln (c.10925G>A)?

ANK2 p.Arg3642Gln (c.10925G>A) is associated with long QT syndrome (ClinVar).

How common is ANK2 p.Arg3642Gln (c.10925G>A) in the general population?

ANK2 p.Arg3642Gln (c.10925G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ANK2 p.Arg3642Gln (c.10925G>A)?

AlphaMissense predicts likely pathogenic (score 0.978) — an in-silico prediction, not a clinical call.

ANK2 p.Arg3642Gln

c.10925G>A · rs757939990 · VCV2151081

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.978 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

long QT syndrome

Computational evidence

Protein change
AlphaMissense	0.978	likely pathogenic
REVEL	0.744	pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
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 0.97	unconstrained · MANE · 28 kb · p 0.16 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000682% 11/1,613,704 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00445%	22,447
South Asian	0.0022%	45,542
European (non-Finnish)	0.000509%	196,637

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.Arg3642Gln
Coding: c.10925G>A
MANE Select: NM_001148
dbSNP: rs757939990
Type: single nucleotide variant
Location: chr4:113365075 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 3642: the death 2 domain

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.Arg3642= Likely benign ★★ same residue
ANK2 p.Arg3642Ter Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg3642gln (accessed [today's date]).

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