Is ANK2 p.Ser2657= (c.7971C>T) pathogenic?

ANK2 p.Ser2657= (c.7971C>T) is classified Benign/Likely benign in ANK2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-02). Rare (popmax 0.234%, afr); Associated with cardiac arrhythmia, ankyrin-B-related.

What condition is associated with ANK2 p.Ser2657= (c.7971C>T)?

ANK2 p.Ser2657= (c.7971C>T) is associated with cardiac arrhythmia, ankyrin-B-related, long QT syndrome (ClinVar).

How common is ANK2 p.Ser2657= (c.7971C>T) in the general population?

ANK2 p.Ser2657= (c.7971C>T) is rare (popmax 0.234%, 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 p.Ser2657=

c.7971C>T · rs146085234 · VCV506540

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.234%, 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 1.8	GERP 1.9, phastCons 1
Overall
CADD	5.723	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.234% African / African-American · 175/74,902 alleles

Filtering AF 0.205% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.194%

Overall 0.0115% 186/1,613,958 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.234%	428
Remaining individualsnot grpmax-eligible	0.0112%	8,927
Admixed American	0.005%	19,999
European (non-Finnish)	8.47e-05%	1,179,986

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.Ser2657=
Coding: c.7971C>T
MANE Select: NM_001148
dbSNP: rs146085234
Type: single nucleotide variant
Location: chr4:113356589 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2657: the 'disordered' region

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

Also linked: long QT syndrome

For Romano-Ward syndrome (Orphanet):

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

Similar variants

ANK2 p.Ser2657Gly Uncertain significance ★★ ⚠ same residue
ANK2 p.Ser2657Asn Uncertain significance ★ ⚠ same residue
ANK2 p.Arg1007Ter Pathogenic/Likely pathogenic ★★ same condition
ANK2 p.Arg1088Ter Pathogenic ★★ same condition
ANK2 p.Arg3113Ter Pathogenic ★★ same condition
ANK2 c.11032+11G>T Uncertain significance ★★ same condition
ANK2 c.11611-3T>A Uncertain significance ★★ same condition
ANK2 c.1783-3C>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-ser2657 (accessed [today's date]).

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