Is ANK2 p.Ile2285Thr (c.6854T>C) pathogenic?

ANK2 p.Ile2285Thr (c.6854T>C) is classified Conflicting classifications of pathogenicity in ANK2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-14). AlphaMissense: likely benign (0.0964); Ultra-rare (popmax 0.0242%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with ANK2 p.Ile2285Thr (c.6854T>C)?

ANK2 p.Ile2285Thr (c.6854T>C) is associated with Cardiovascular phenotype, long QT syndrome, cardiomyopathy (ClinVar).

How common is ANK2 p.Ile2285Thr (c.6854T>C) in the general population?

ANK2 p.Ile2285Thr (c.6854T>C) is ultra-rare (popmax 0.0242%, nfe) (gnomAD).

What do computational predictors say about ANK2 p.Ile2285Thr (c.6854T>C)?

AlphaMissense predicts likely benign (score 0.0964) — an in-silico prediction, not a clinical call.

ANK2 p.Ile2285Thr

c.6854T>C · rs150684838 · VCV191539

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0964 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0964	likely benign
REVEL	0.076	moderately 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 -1.2	GERP -4.8
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.16 · regional, not allelic
Overall
CADD	0.112	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 0.0242% European (non-Finnish) · 285/1,179,976 alleles

Filtering AF 0.0218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.0189% 305/1,613,800 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0242%	4,140
Admixed American	0.0117%	8,569
Remaining individualsnot grpmax-eligible	0.0112%	8,926
African / African-American	0.00668%	14,970
Finnishnot grpmax-eligible	0.00156%	63,958

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.Ile2285Thr
Coding: c.6854T>C
MANE Select: NM_001148
dbSNP: rs150684838
Type: single nucleotide variant
Location: chr4:113355472 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2285: 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 cardiomyopathy

Similar variants

ANK2 p.Arg3113Ter Pathogenic ★★ same condition
ANK2 p.Arg895Ter Pathogenic/Likely pathogenic ★★ same condition
ANK2 p.Arg977Ter Pathogenic ★★ same condition
ANK2 c.11611-3T>A Uncertain significance ★★ same condition
ANK2 c.1783-3C>T Uncertain significance ★★ same condition
ANK2 c.2079+5T>G Uncertain significance ★★ same condition
ANK2 c.2278-3C>T Uncertain significance ★★ same condition
ANK2 c.3125+6G>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-ile2285thr (accessed [today's date]).

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