Is ANK2 p.Arg1088Ter (c.3262C>T) pathogenic?

ANK2 p.Arg1088Ter (c.3262C>T) is classified Pathogenic in ANK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-19). Very rare (popmax 8.47e-05%, nfe); Associated with ANK2-associated Neurodevelopmental Disorder.

How common is ANK2 p.Arg1088Ter (c.3262C>T) in the general population?

ANK2 p.Arg1088Ter (c.3262C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

ANK2 p.Arg1088Ter

Q: What condition is associated with ANK2 p.Arg1088Ter (c.3262C>T)?

ANK2 p.Arg1088Ter (c.3262C>T) is associated with ANK2-associated Neurodevelopmental Disorder, cardiac arrhythmia, ankyrin-B-related (ClinVar).

c.3262C>T · rs2153942439 · VCV2576605

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

ANK2-associated Neurodevelopmental 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 29 of 46
REVEL	0.173	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.25	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 2.7	GERP 1.6, phastCons 0.99
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 8.47e-05% European (non-Finnish) · 1/1,180,016 alleles

Overall 0.000137% 2/1,461,886 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)grpmax	8.47e-05%	1,180,016

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1088Ter
Coding: c.3262C>T
MANE Select: NM_001148
dbSNP: rs2153942439
Type: single nucleotide variant
Location: chr4:113333091 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1088: a turn; 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

ANK2-associated Neurodevelopmental Disorder

Also linked: cardiac arrhythmia, ankyrin-B-related

Similar variants

ANK2 p.Arg1088Gln Uncertain significance ★★ same residue
ANK2 p.Arg1007Ter Pathogenic/Likely pathogenic ★★ same condition
ANK2 p.Arg888Ter Pathogenic/Likely pathogenic ★★ same condition
ANK2 c.11032+11G>T Uncertain significance ★★ same condition
ANK2 c.2900+5141G>A Uncertain significance ★★ same condition
ANK2 c.85-28508A>G Uncertain significance ★★ same condition
ANK2 c.85-57022A>C Uncertain significance ★★ same condition
ANK2 c.*1950C>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-arg1088ter (accessed [today's date]).

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