Is ANK2 p.Ser2156Arg (c.6468T>G) pathogenic?

ANK2 p.Ser2156Arg (c.6468T>G) is classified Likely benign in ANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-13). AlphaMissense: likely benign (0.2239); Very rare (popmax 0.0011%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with ANK2 p.Ser2156Arg (c.6468T>G)?

ANK2 p.Ser2156Arg (c.6468T>G) is associated with Cardiovascular phenotype (ClinVar).

How common is ANK2 p.Ser2156Arg (c.6468T>G) in the general population?

ANK2 p.Ser2156Arg (c.6468T>G) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about ANK2 p.Ser2156Arg (c.6468T>G)?

AlphaMissense predicts likely benign (score 0.2239) — an in-silico prediction, not a clinical call.

ANK2 p.Ser2156Arg

c.6468T>G · rs1227639389 · VCV1753691

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2239 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2239	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.7	GERP -5.7
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.16 · regional, not allelic
Overall
CADD	5.587	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,179,916 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000806% 13/1,613,600 alleles · very rare exomes 12/1,461,808 · genomes 1/151,792 · joint denominator

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.Ser2156Arg
Coding: c.6468T>G
MANE Select: NM_001148
dbSNP: rs1227639389
Type: single nucleotide variant
Location: chr4:113355086 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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 p.Ala1152Val Uncertain significance ★★ ⚠ same condition
ANK2 p.Ala1214Thr 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-ser2156arg (accessed [today's date]).

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