Is ANK2 p.Arg321Trp (c.961C>T) pathogenic?

ANK2 p.Arg321Trp (c.961C>T) is classified Uncertain significance in ANK2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-03-23). AlphaMissense: ambiguous (0.4264); Ultra-rare (popmax 0.0187%, afr); Associated with Cardiovascular phenotype.

What condition is associated with ANK2 p.Arg321Trp (c.961C>T)?

ANK2 p.Arg321Trp (c.961C>T) is associated with Cardiovascular phenotype, long QT syndrome, Brugada syndrome (ClinVar).

How common is ANK2 p.Arg321Trp (c.961C>T) in the general population?

ANK2 p.Arg321Trp (c.961C>T) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

What do computational predictors say about ANK2 p.Arg321Trp (c.961C>T)?

AlphaMissense predicts ambiguous (score 0.4264) — an in-silico prediction, not a clinical call.

ANK2 p.Arg321Trp

c.961C>T · rs753032598 · VCV190539

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4264 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4264	ambiguous
REVEL	0.546	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -0.1, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 24 kb · p 3.4e-14 · regional, not allelic
Overall
CADD	27.5	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 0.0187% African / African-American · 14/74,944 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00904%

Overall 0.00632% 102/1,614,016 alleles · ultra-rare exomes 88/1,461,788 · genomes 14/152,228 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,353
European (non-Finnish)	0.00703%	14,217
Remaining individualsnot grpmax-eligible	0.0032%	31,239
East Asian	0.00223%	44,888
Admixed American	0.00167%	60,004
South Asian	0.0011%	91,032

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.Arg321Trp
Coding: c.961C>T
MANE Select: NM_001148
dbSNP: rs753032598
Type: single nucleotide variant
Location: chr4:113249833 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

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 Brugada syndrome

Similar variants

ANK2 p.Arg321Gln Benign/Likely benign ★★ same residue
ANK2 p.Arg321= Likely benign ★ 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-arg321trp (accessed [today's date]).

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