Is ANK2 p.Ala1152Val (c.3455C>T) pathogenic?

ANK2 p.Ala1152Val (c.3455C>T) is classified Uncertain significance in ANK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-03). AlphaMissense: likely pathogenic (0.9458); Very rare (popmax 0.00119%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with ANK2 p.Ala1152Val (c.3455C>T)?

ANK2 p.Ala1152Val (c.3455C>T) is associated with Cardiovascular phenotype, long QT syndrome (ClinVar).

How common is ANK2 p.Ala1152Val (c.3455C>T) in the general population?

ANK2 p.Ala1152Val (c.3455C>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about ANK2 p.Ala1152Val (c.3455C>T)?

AlphaMissense predicts likely pathogenic (score 0.9458) — an in-silico prediction, not a clinical call.

ANK2 p.Ala1152Val

c.3455C>T · rs376536631 · VCV1433961

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9458 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9458	likely pathogenic
REVEL	0.711	pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 98 kb · p 4.4e-21 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00119% European (non-Finnish) · 14/1,180,032 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000867% 14/1,613,994 alleles · very rare

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.Ala1152Val
Coding: c.3455C>T
MANE Select: NM_001148
dbSNP: rs376536631
Type: single nucleotide variant
Location: chr4:113335921 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1152: the zu5 1 domain; a β-strand

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

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-ala1152val (accessed [today's date]).

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