Is ANK2 p.Phe3129Cys (c.9386T>G) pathogenic?

ANK2 p.Phe3129Cys (c.9386T>G) is classified Uncertain significance in ANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: ambiguous (0.4195); Absent from gnomAD v4.1; Associated with cardiac arrhythmia, ankyrin-B-related.

What condition is associated with ANK2 p.Phe3129Cys (c.9386T>G)?

ANK2 p.Phe3129Cys (c.9386T>G) is associated with cardiac arrhythmia, ankyrin-B-related (ClinVar).

How common is ANK2 p.Phe3129Cys (c.9386T>G) in the general population?

ANK2 p.Phe3129Cys (c.9386T>G) is absent from gnomAD v4.1 (gnomAD).

How is Romano-Ward syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ANK2 p.Phe3129Cys (c.9386T>G)?

AlphaMissense predicts ambiguous (score 0.4195) — an in-silico prediction, not a clinical call.

ANK2 p.Phe3129Cys

c.9386T>G · rs2095907660 · VCV899415

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4195 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

cardiac arrhythmia, ankyrin-B-related

Computational evidence

Protein change
AlphaMissense	0.4195	ambiguous
REVEL	0.698	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.16 · regional, not allelic
Overall
CADD	24.2	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.Phe3129Cys
Coding: c.9386T>G
MANE Select: NM_001148
dbSNP: rs2095907660
Type: single nucleotide variant
Location: chr4:113358004 (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

cardiac arrhythmia, ankyrin-B-related — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Romano-Ward syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ANK2 p.Phe3129= Likely benign ★ same residue
ANK2 p.Arg1007Ter Pathogenic/Likely pathogenic ★★ same condition
ANK2 p.Arg1088Ter Pathogenic ★★ same condition
ANK2 c.11032+11G>T Uncertain significance ★★ same condition
ANK2 c.2900+5141G>A Uncertain significance ★★ same condition
ANK2 c.*1950C>A Uncertain significance ★★ same condition
ANK2 p.Ala178Val Uncertain significance ★★ ⚠ same condition
ANK2 p.Ala3485Thr 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-phe3129cys (accessed [today's date]).

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