Is ANK2 p.Gly53Trp (c.157G>T) pathogenic?

ANK2 p.Gly53Trp (c.157G>T) is classified Uncertain significance in ANK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-08). AlphaMissense: likely pathogenic (0.7048); Ultra-rare (popmax 0.0165%, mid); Associated with long QT syndrome.

What condition is associated with ANK2 p.Gly53Trp (c.157G>T)?

ANK2 p.Gly53Trp (c.157G>T) is associated with long QT syndrome, cardiac arrhythmia, ankyrin-B-related (ClinVar).

How common is ANK2 p.Gly53Trp (c.157G>T) in the general population?

ANK2 p.Gly53Trp (c.157G>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ANK2 p.Gly53Trp (c.157G>T)?

AlphaMissense predicts likely pathogenic (score 0.7048) — an in-silico prediction, not a clinical call.

ANK2 p.Gly53Trp

c.157G>T · rs1328490060 · VCV930928

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7048 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

long QT syndrome

Computational evidence

Protein change
AlphaMissense	0.7048	likely pathogenic
REVEL	0.306	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 0.63, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 183 kb · p 0.11 · regional, not allelic
Overall
CADD	28.1	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 0.0165% Middle Eastern · 1/6,074 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000434% 7/1,612,702 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,074
African / African-American	0.00267%	37,449
European (non-Finnish)	0.000339%	294,812

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.Gly53Trp
Coding: c.157G>T
MANE Select: NM_001148
dbSNP: rs1328490060
Type: single nucleotide variant
Location: chr4:113174488 (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

Also linked: cardiac arrhythmia, ankyrin-B-related

Similar variants

ANK2 p.Gly53Ala Uncertain significance ★★ ⚠ same residue
ANK2 p.Gly53Arg Uncertain significance ★ ⚠ same residue
ANK2 p.Arg1007Ter Pathogenic/Likely pathogenic ★★ same condition
ANK2 p.Arg1088Ter Pathogenic ★★ same condition
ANK2 p.Arg3113Ter Pathogenic ★★ same condition
ANK2 c.11032+11G>T Uncertain significance ★★ 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-gly53trp (accessed [today's date]).

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