Is ANK2 p.Ala1027Asp (c.3080C>A) pathogenic?

ANK2 p.Ala1027Asp (c.3080C>A) is classified Uncertain significance in ANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely pathogenic (0.9522); Very rare (popmax 0.000254%, nfe); Associated with neurodevelopmental disorder.

What condition is associated with ANK2 p.Ala1027Asp (c.3080C>A)?

ANK2 p.Ala1027Asp (c.3080C>A) is associated with neurodevelopmental disorder (ClinVar).

How common is ANK2 p.Ala1027Asp (c.3080C>A) in the general population?

ANK2 p.Ala1027Asp (c.3080C>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ANK2 p.Ala1027Asp (c.3080C>A)?

AlphaMissense predicts likely pathogenic (score 0.9522) — an in-silico prediction, not a clinical call.

ANK2 p.Ala1027Asp

c.3080C>A · VCV4531920

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9522 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.9522	likely pathogenic
REVEL	0.601	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 98 kb · p 4.4e-21 · regional, not allelic
Overall
CADD	28.3	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 0.000254% European (non-Finnish) · 3/1,180,034 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,876 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.Ala1027Asp
Coding: c.3080C>A
MANE Select: NM_001148
Type: single nucleotide variant
Location: chr4:113330425 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1027: a β-strand; 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

neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ANK2 p.Met1988Thr Uncertain significance ★★ ⚠ same condition
ANK2 p.Glu1460Ter Pathogenic ★ same condition
ANK2 p.Arg1305Ter Conflicting classifications of pathogenicity ★ ⚠ same condition
ANK2 p.Asp3180fs Pathogenic ★ same condition
ANK2 p.Gly2083fs Pathogenic ★ same condition
ANK2 p.Leu3438fs Pathogenic ★ same condition
ANK2 p.Ser1879fs Pathogenic ★ same condition
ANK2 p.Arg1007Ter Pathogenic/Likely pathogenic ★★ same type

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-ala1027asp (accessed [today's date]).

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