Is ANK2 p.Arg379Cys (c.1135C>T) pathogenic?

ANK2 p.Arg379Cys (c.1135C>T) is classified Benign/Likely benign in ANK2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-02). AlphaMissense: likely pathogenic (0.6431); Rare (popmax 0.53%, sas); Associated with Cardiovascular phenotype.

What condition is associated with ANK2 p.Arg379Cys (c.1135C>T)?

ANK2 p.Arg379Cys (c.1135C>T) is associated with Cardiovascular phenotype, long QT syndrome, cardiac arrhythmia, ankyrin-B-related (ClinVar).

How common is ANK2 p.Arg379Cys (c.1135C>T) in the general population?

ANK2 p.Arg379Cys (c.1135C>T) is rare (popmax 0.53%, sas) (gnomAD).

What do computational predictors say about ANK2 p.Arg379Cys (c.1135C>T)?

AlphaMissense predicts likely pathogenic (score 0.6431) — an in-silico prediction, not a clinical call.

ANK2 p.Arg379Cys

c.1135C>T · rs143043717 · VCV190542

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.6431 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.53%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.6431	likely pathogenic
REVEL	0.53	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.73, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 98 kb · p 4.4e-21 · regional, not allelic
Overall
CADD	32.0	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 0.53% South Asian · 483/91,080 alleles

Filtering AF 0.491% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.476%

Overall 0.0346% 558/1,614,160 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.53%	189
Remaining individualsnot grpmax-eligible	0.0304%	3,290
Middle Eastern	0.0165%	6,062
East Asian	0.0156%	6,412
European (non-Finnish)	0.0039%	25,653
Admixed American	0.00167%	60,030
African / African-American	0.00133%	75,010

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.Arg379Cys
Coding: c.1135C>T
MANE Select: NM_001148
dbSNP: rs143043717
Type: single nucleotide variant
Location: chr4:113255879 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 379: 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 cardiac arrhythmia, ankyrin-B-related

Similar variants

ANK2 p.Arg379His Uncertain significance ★★ same residue
ANK2 p.Arg379Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
ANK2 p.Arg1007Ter Pathogenic/Likely pathogenic ★★ same condition
ANK2 p.Arg1088Ter Pathogenic ★★ same condition
ANK2 p.Arg3113Ter Pathogenic ★★ same condition
ANK2 p.Arg895Ter Pathogenic/Likely pathogenic ★★ same condition
ANK2 p.Arg977Ter Pathogenic ★★ same condition
ANK2 c.11032+11G>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-arg379cys (accessed [today's date]).

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