Is ANK2 p.Arg3659Leu (c.10976G>T) pathogenic?

ANK2 p.Arg3659Leu (c.10976G>T) is classified Conflicting classifications of pathogenicity in ANK2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-10-25). AlphaMissense: likely benign (0.1685); Ultra-rare (popmax 0.0825%, mid); Associated with ANK2-related disorder.

What condition is associated with ANK2 p.Arg3659Leu (c.10976G>T)?

ANK2 p.Arg3659Leu (c.10976G>T) is associated with ANK2-related disorder, long QT syndrome, cardiac arrhythmia, ankyrin-B-related (ClinVar).

How common is ANK2 p.Arg3659Leu (c.10976G>T) in the general population?

ANK2 p.Arg3659Leu (c.10976G>T) is ultra-rare (popmax 0.0825%, mid) (gnomAD).

What do computational predictors say about ANK2 p.Arg3659Leu (c.10976G>T)?

AlphaMissense predicts likely benign (score 0.1685) — an in-silico prediction, not a clinical call.

ANK2 p.Arg3659Leu

c.10976G>T · rs556640912 · VCV377479

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1685 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0825%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

ANK2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1685	likely benign
REVEL	0.257	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -2.2, phastCons 0.83
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.16 · regional, not allelic
Overall
CADD	20.7	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 0.0825% Middle Eastern · 5/6,062 alleles

Filtering AF 0.0643% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.059%

Overall 0.00954% 154/1,613,902 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0825%	1,212
South Asian	0.0791%	1,265
Remaining individualsnot grpmax-eligible	0.024%	4,167
European (non-Finnish)	0.00509%	19,666
Admixed American	0.00167%	59,994
African / African-American	0.00133%	74,974

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.Arg3659Leu
Coding: c.10976G>T
MANE Select: NM_001148
dbSNP: rs556640912
Type: single nucleotide variant
Location: chr4:113365126 (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

ANK2-related disorder

Also linked: long QT syndrome cardiac arrhythmia, ankyrin-B-related

Similar variants

ANK2 p.Arg3659Cys Conflicting classifications of pathogenicity ★ same residue
ANK2 p.Arg3659His 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.Arg888Ter Pathogenic/Likely 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-arg3659leu (accessed [today's date]).

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