Is ANK2 p.Arg1418Ser (c.4252C>A) pathogenic?

ANK2 p.Arg1418Ser (c.4252C>A) is classified Uncertain significance in ANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-13). AlphaMissense: likely pathogenic (0.9975); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with ANK2 p.Arg1418Ser (c.4252C>A)?

ANK2 p.Arg1418Ser (c.4252C>A) is associated with Cardiovascular phenotype (ClinVar).

How common is ANK2 p.Arg1418Ser (c.4252C>A) in the general population?

ANK2 p.Arg1418Ser (c.4252C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ANK2 p.Arg1418Ser (c.4252C>A)?

AlphaMissense predicts likely pathogenic (score 0.9975) — an in-silico prediction, not a clinical call.

ANK2 p.Arg1418Ser

c.4252C>A · rs749093363 · VCV2537041

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9975 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9975	likely pathogenic · top 3% in ANK2
REVEL	0.418	indeterminate
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.67 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 2.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 98 kb · p 4.4e-21 · regional, not allelic
Overall
CADD	25.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ANK2
Protein: p.Arg1418Ser
Coding: c.4252C>A
MANE Select: NM_001148
dbSNP: rs749093363
Type: single nucleotide variant
Location: chr4:113345903 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1418: a β-strand; the 'upa domain' 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

Similar variants

ANK2 p.Arg1418His Uncertain significance ★★ same residue
ANK2 p.Arg1418= Likely benign ★★ same residue
ANK2 p.Arg1418Cys 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

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-arg1418ser (accessed [today's date]).

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