Is ANK2 p.Phe261Leu (c.781T>C) pathogenic?

ANK2 p.Phe261Leu (c.781T>C) is classified Uncertain significance in ANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-08). AlphaMissense: likely pathogenic (0.9986); Absent from gnomAD v4.1; Associated with long QT syndrome.

What condition is associated with ANK2 p.Phe261Leu (c.781T>C)?

ANK2 p.Phe261Leu (c.781T>C) is associated with long QT syndrome (ClinVar).

How common is ANK2 p.Phe261Leu (c.781T>C) in the general population?

ANK2 p.Phe261Leu (c.781T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ANK2 p.Phe261Leu (c.781T>C)?

AlphaMissense predicts likely pathogenic (score 0.9986) — an in-silico prediction, not a clinical call.

ANK2 p.Phe261Leu

c.781T>C · rs1563105054 · VCV573423

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9986 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

long QT syndrome

Computational evidence

Protein change
AlphaMissense	0.9986	likely pathogenic · top 2% in ANK2
REVEL	0.422	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP 2.5, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 24 kb · p 3.4e-14 · regional, not allelic
Overall
CADD	28.6	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

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.Phe261Leu
Coding: c.781T>C
MANE Select: NM_001148
dbSNP: rs1563105054
Type: single nucleotide variant
Location: chr4:113240572 (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

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

Similar variants

ANK2 p.Arg3113Ter 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
ANK2 c.693+6G>A Uncertain significance ★★ same condition
ANK2 c.85-3C>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-phe261leu (accessed [today's date]).

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