Is ANK2 p.Arg996Trp (c.2986C>T) pathogenic?

ANK2 p.Arg996Trp (c.2986C>T) is classified Uncertain significance in ANK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-14). AlphaMissense: likely pathogenic (0.9258); Very rare (popmax 0.00329%, sas); Associated with long QT syndrome.

What condition is associated with ANK2 p.Arg996Trp (c.2986C>T)?

ANK2 p.Arg996Trp (c.2986C>T) is associated with long QT syndrome (ClinVar).

How common is ANK2 p.Arg996Trp (c.2986C>T) in the general population?

ANK2 p.Arg996Trp (c.2986C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about ANK2 p.Arg996Trp (c.2986C>T)?

AlphaMissense predicts likely pathogenic (score 0.9258) — an in-silico prediction, not a clinical call.

ANK2 p.Arg996Trp

c.2986C>T · rs1393086626 · VCV1316468

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9258 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

long QT syndrome

Computational evidence

Protein change
AlphaMissense	0.9258	likely pathogenic
REVEL	0.411	indeterminate
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.1	GERP 1.6, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 98 kb · p 4.4e-21 · regional, not allelic
Overall
CADD	29.5	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 0.00329% South Asian · 3/91,084 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000743% 12/1,614,088 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,361
European (non-Finnish)	0.000763%	131,116

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.Arg996Trp
Coding: c.2986C>T
MANE Select: NM_001148
dbSNP: rs1393086626
Type: single nucleotide variant
Location: chr4:113330331 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 996: the zu5 1 domain; the 'interaction with sptbn1' region

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.Arg996Gln Uncertain significance ★★ same residue
ANK2 p.Arg996= Likely benign ★ same residue
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

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-arg996trp (accessed [today's date]).

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