Is ANK2 c.*446T>C pathogenic?

ANK2 c.446T>C is classified Benign in ANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Low-frequency (popmax 2.56%, afr); Associated with cardiac arrhythmia, ankyrin-B-related.

What condition is associated with ANK2 c.*446T>C?

ANK2 c.*446T>C is associated with cardiac arrhythmia, ankyrin-B-related (ClinVar).

How common is ANK2 c.*446T>C in the general population?

ANK2 c.*446T>C is low-frequency (popmax 2.56%, afr) (gnomAD).

How is Romano-Ward syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ANK2 c.*446T>C

rs114488000 · VCV347354

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

low-frequency (popmax 2.56%, afr)

Conditions

cardiac arrhythmia, ankyrin-B-related

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -2.5, phastCons 1
Non-coding constraint	Z 0.76	1 kb window · o/e 0.94 · regional · uncalibrated
Overall
CADD	9.385	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.56% African / African-American · 1,207/47,084 alleles

Filtering AF 2.44% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.39%

Overall 0.369% 1,282/347,102 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.56%	39
Admixed American	0.19%	527
Remaining individualsnot grpmax-eligible	0.136%	736
European (non-Finnish)	0.00453%	22,052
South Asian	0.00239%	41,840

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
Coding: c.*446T>C
MANE Select: NM_001148
dbSNP: rs114488000
Type: single nucleotide variant
Location: chr4:113381917 (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

cardiac arrhythmia, ankyrin-B-related — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Romano-Ward syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ANK2 p.Arg1007Ter Pathogenic/Likely pathogenic ★★ same condition
ANK2 p.Arg1088Ter Pathogenic ★★ same condition
ANK2 c.11032+11G>T Uncertain significance ★★ same condition
ANK2 c.2900+5141G>A Uncertain significance ★★ same condition
ANK2 c.*1950C>A Uncertain significance ★★ same condition
ANK2 p.Ala178Val Uncertain significance ★★ ⚠ same condition
ANK2 p.Ala3485Thr Uncertain significance ★★ same condition
ANK2 p.Ala373Val 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-c-star-446t-c (accessed [today's date]).

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