Is ANK2 p.Ala1744Asp (c.5231C>A) pathogenic?

ANK2 p.Ala1744Asp (c.5231C>A) is classified Conflicting classifications of pathogenicity in ANK2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-21). AlphaMissense: likely benign (0.1385); Ultra-rare (popmax 0.0126%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with ANK2 p.Ala1744Asp (c.5231C>A)?

ANK2 p.Ala1744Asp (c.5231C>A) is associated with Cardiovascular phenotype, intellectual disability, long QT syndrome (ClinVar).

How common is ANK2 p.Ala1744Asp (c.5231C>A) in the general population?

ANK2 p.Ala1744Asp (c.5231C>A) is ultra-rare (popmax 0.0126%, nfe) (gnomAD).

What do computational predictors say about ANK2 p.Ala1744Asp (c.5231C>A)?

AlphaMissense predicts likely benign (score 0.1385) — an in-silico prediction, not a clinical call.

ANK2 p.Ala1744Asp

c.5231C>A · rs147706514 · VCV264303

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1385 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0126%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1385	likely benign
REVEL	0.247	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 1.1	GERP 0.87, phastCons 0.24
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.16 · regional, not allelic
Overall
CADD	19.82	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 0.0126% European (non-Finnish) · 149/1,179,956 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0103%

Overall 0.00954% 154/1,613,782 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0126%	7,919
Remaining individualsnot grpmax-eligible	0.0032%	31,237
African / African-American	0.00267%	37,434
Admixed American	0.00167%	59,972

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.Ala1744Asp
Coding: c.5231C>A
MANE Select: NM_001148
dbSNP: rs147706514
Type: single nucleotide variant
Location: chr4:113353849 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1744: 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: intellectual disability long QT syndrome

Similar variants

ANK2 p.Ala1744Thr Uncertain significance ★★ ⚠ same residue
ANK2 p.Ala1744Val Uncertain significance ★ ⚠ same residue
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

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-ala1744asp (accessed [today's date]).

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