Is ANK2 p.Arg3058His (c.9173G>A) pathogenic?

ANK2 p.Arg3058His (c.9173G>A) is classified Uncertain significance in ANK2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-12-29). AlphaMissense: likely pathogenic (0.5923); Very rare (popmax 0.00134%, afr); Associated with long QT syndrome.

What condition is associated with ANK2 p.Arg3058His (c.9173G>A)?

ANK2 p.Arg3058His (c.9173G>A) is associated with long QT syndrome, cardiac arrhythmia, ankyrin-B-related (ClinVar).

How common is ANK2 p.Arg3058His (c.9173G>A) in the general population?

ANK2 p.Arg3058His (c.9173G>A) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about ANK2 p.Arg3058His (c.9173G>A)?

AlphaMissense predicts likely pathogenic (score 0.5923) — an in-silico prediction, not a clinical call.

ANK2 p.Arg3058His

c.9173G>A · rs730880048 · VCV180273

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.5923 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

long QT syndrome

Computational evidence

Protein change
AlphaMissense	0.5923	likely pathogenic
REVEL	0.535	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.16 · regional, not allelic
Overall
CADD	27.9	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 0.00134% African / African-American · 1/74,892 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,613,816 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-Americangrpmax	0.00134%	74,892
European (non-Finnish)	0.000424%	235,988

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg3058His
Coding: c.9173G>A
MANE Select: NM_001148
dbSNP: rs730880048
Type: single nucleotide variant
Location: chr4:113357791 (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

long QT syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiac arrhythmia, ankyrin-B-related

Similar variants

ANK2 p.Arg3058Cys Conflicting classifications of pathogenicity ★ same residue
ANK2 p.Arg3058Ser Uncertain significance ★ same residue
ANK2 p.Arg3058= 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 c.11032+11G>T Uncertain significance ★★ same condition
ANK2 c.11611-3T>A 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-arg3058his (accessed [today's date]).

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