Is ANK2 p.Pro2967Ala (c.8899C>G) pathogenic?

ANK2 p.Pro2967Ala (c.8899C>G) is classified Conflicting classifications of pathogenicity in ANK2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-03-06). AlphaMissense: likely benign (0.0497); Very rare (popmax 8.47e-05%, nfe); Associated with Brugada syndrome.

What condition is associated with ANK2 p.Pro2967Ala (c.8899C>G)?

ANK2 p.Pro2967Ala (c.8899C>G) is associated with Brugada syndrome (ClinVar).

How common is ANK2 p.Pro2967Ala (c.8899C>G) in the general population?

ANK2 p.Pro2967Ala (c.8899C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Brugada syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ANK2 p.Pro2967Ala (c.8899C>G)?

AlphaMissense predicts likely benign (score 0.0497) — an in-silico prediction, not a clinical call.

ANK2 p.Pro2967Ala

c.8899C>G · rs2505905528 · VCV1765013

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0497 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Brugada syndrome

Computational evidence

Protein change
AlphaMissense	0.0497	likely benign
REVEL	0.052	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 -0.003	GERP -3.6, phastCons 0.017
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.16 · regional, not allelic
Overall
CADD	0.359	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 8.47e-05% European (non-Finnish) · 1/1,179,974 alleles

Overall 6.84e-05% 1/1,461,826 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.Pro2967Ala
Coding: c.8899C>G
MANE Select: NM_001148
dbSNP: rs2505905528
Type: single nucleotide variant
Location: chr4:113357517 (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

Brugada syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Brugada syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ANK2 p.Pro2967Leu Uncertain significance ★★ ⚠ same residue
ANK2 p.Ala209Ser Uncertain significance ★★ ⚠ same condition
ANK2 p.Arg321Trp Uncertain significance ★★ same condition
ANK2 p.Arg3942His Uncertain significance ★★ ⚠ same condition
ANK2 p.Ser2250Leu Likely pathogenic ★ ⚠ same condition
ANK2 c.11859+1402A>T Uncertain significance ★ same condition
ANK2 c.85-57113C>A Uncertain significance ★ same condition
ANK2 p.Asn687Ser Conflicting classifications of pathogenicity ★ ⚠ 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-pro2967ala (accessed [today's date]).

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