Is ANK2 p.Arg37Cys (c.109C>T) pathogenic?

ANK2 p.Arg37Cys (c.109C>T) is classified Uncertain significance in ANK2 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-06-08). AlphaMissense: likely pathogenic (0.9957); Very rare (popmax 0.000254%, nfe); Associated with cardiac arrhythmia, ankyrin-B-related.

What condition is associated with ANK2 p.Arg37Cys (c.109C>T)?

ANK2 p.Arg37Cys (c.109C>T) is associated with cardiac arrhythmia, ankyrin-B-related (ClinVar).

How common is ANK2 p.Arg37Cys (c.109C>T) in the general population?

ANK2 p.Arg37Cys (c.109C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is Romano-Ward syndrome inherited?

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

What do computational predictors say about ANK2 p.Arg37Cys (c.109C>T)?

AlphaMissense predicts likely pathogenic (score 0.9957) — an in-silico prediction, not a clinical call.

ANK2 p.Arg37Cys

c.109C>T · rs369877280 · VCV1186234

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9957 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

cardiac arrhythmia, ankyrin-B-related

Computational evidence

Protein change
AlphaMissense	0.9957	likely pathogenic · top 5% in ANK2
REVEL	0.51	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP 0.63, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 183 kb · p 0.11 · regional, not allelic
Overall
CADD	31.0	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 0.000254% European (non-Finnish) · 3/1,179,316 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,612,828 alleles · very rare exomes 2/1,460,676 · genomes 1/152,152 · joint denominator

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.Arg37Cys
Coding: c.109C>T
MANE Select: NM_001148
dbSNP: rs369877280
Type: single nucleotide variant
Location: chr4:113174440 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 37: an α-helix

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-p-arg37cys (accessed [today's date]).

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