Is ANK2 p.Arg3454Ser (c.10362G>T) pathogenic?

ANK2 p.Arg3454Ser (c.10362G>T) is classified Likely benign in ANK2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1882); Rare (popmax 0.12%, afr); Associated with Cardiovascular phenotype.

What condition is associated with ANK2 p.Arg3454Ser (c.10362G>T)?

ANK2 p.Arg3454Ser (c.10362G>T) is associated with Cardiovascular phenotype, long QT syndrome, cardiac arrhythmia, ankyrin-B-related (ClinVar).

How common is ANK2 p.Arg3454Ser (c.10362G>T) in the general population?

ANK2 p.Arg3454Ser (c.10362G>T) is rare (popmax 0.12%, afr) (gnomAD).

What do computational predictors say about ANK2 p.Arg3454Ser (c.10362G>T)?

AlphaMissense predicts likely benign (score 0.1882) — an in-silico prediction, not a clinical call.

ANK2 p.Arg3454Ser

c.10362G>T · rs55726422 · VCV406495

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1882 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.12%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1882	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.95	GERP -3.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.16 · regional, not allelic
Overall
CADD	18.64	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 0.12% African / African-American · 90/75,020 alleles

Filtering AF 0.0999% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0925%

Overall 0.00663% 107/1,614,068 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.12%	834
Middle Eastern	0.0165%	6,062
Admixed American	0.015%	6,668
Remaining individualsnot grpmax-eligible	0.0064%	15,627
South Asian	0.0011%	91,084
European (non-Finnish)	0.000169%	589,988

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.Arg3454Ser
Coding: c.10362G>T
MANE Select: NM_001148
dbSNP: rs55726422
Type: single nucleotide variant
Location: chr4:113358980 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 3454: the 'disordered' region

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.Arg3454Lys Uncertain significance ★ ⚠ same residue
ANK2 p.Arg3454= Likely benign ★ 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-arg3454ser (accessed [today's date]).

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