Is ANK2 p.Arg379His (c.1136G>A) pathogenic?

ANK2 p.Arg379His (c.1136G>A) is classified Uncertain significance in ANK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-12). AlphaMissense: ambiguous (0.4158); Ultra-rare (popmax 0.0156%, eas); Associated with Cardiovascular phenotype.

What condition is associated with ANK2 p.Arg379His (c.1136G>A)?

ANK2 p.Arg379His (c.1136G>A) is associated with Cardiovascular phenotype, long QT syndrome, cardiac arrhythmia, ankyrin-B-related (ClinVar).

How common is ANK2 p.Arg379His (c.1136G>A) in the general population?

ANK2 p.Arg379His (c.1136G>A) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about ANK2 p.Arg379His (c.1136G>A)?

AlphaMissense predicts ambiguous (score 0.4158) — an in-silico prediction, not a clinical call.

ANK2 p.Arg379His

c.1136G>A · rs186264035 · VCV661101

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4158 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4158	ambiguous
REVEL	0.557	indeterminate
Splicing
SpliceAI	Δ0.25	donor gain · deltas
Constraint at this position
Conservation	phyloP 9.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 98 kb · p 4.4e-21 · regional, not allelic
Overall
CADD	34.0	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 0.0156% East Asian · 7/44,884 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00242% 39/1,614,122 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,412
Remaining individualsnot grpmax-eligible	0.0048%	20,837
Admixed American	0.00333%	30,012
European (non-Finnish)	0.00212%	47,201
Finnishnot grpmax-eligible	0.00156%	64,020
South Asian	0.0011%	91,086

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.Arg379His
Coding: c.1136G>A
MANE Select: NM_001148
dbSNP: rs186264035
Type: single nucleotide variant
Location: chr4:113255880 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 379: an α-helix

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.Arg379Cys Benign/Likely benign ★★ same residue
ANK2 p.Arg379Leu Conflicting classifications of pathogenicity ★ ⚠ 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-arg379his (accessed [today's date]).

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