Is ANK2 p.Arg3441Ter (c.10321C>T) pathogenic?

ANK2 p.Arg3441Ter (c.10321C>T) is classified Likely pathogenic in ANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-06). Very rare (popmax 0.0011%, sas); Associated with ANK2-related disorder.

What condition is associated with ANK2 p.Arg3441Ter (c.10321C>T)?

ANK2 p.Arg3441Ter (c.10321C>T) is associated with ANK2-related disorder (ClinVar).

How common is ANK2 p.Arg3441Ter (c.10321C>T) in the general population?

ANK2 p.Arg3441Ter (c.10321C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

ANK2 p.Arg3441Ter

c.10321C>T · VCV4854494

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

ANK2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 38 of 46
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -0.47, phastCons 0.39
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,066 alleles

Overall 6.84e-05% 1/1,461,584 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.Arg3441Ter
Coding: c.10321C>T
MANE Select: NM_001148
Type: single nucleotide variant
Location: chr4:113358939 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 3441: the 'disordered' region

Full ANK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ANK2-related disorder

Similar variants

ANK2 p.Arg3441Gln Likely benign ★★ same residue
ANK2 p.Arg1088Ter Pathogenic ★★ same condition
ANK2 p.Arg888Ter Pathogenic/Likely pathogenic ★★ same condition
ANK2 c.85-28508A>G Uncertain significance ★★ same condition
ANK2 c.85-57022A>C Uncertain significance ★★ same condition
ANK2 p.Ala41Thr Uncertain significance ★★ ⚠ same condition
ANK2 p.Gln2672His Uncertain significance ★★ ⚠ same condition
ANK2 p.Lys114Glu 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-arg3441ter (accessed [today's date]).

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