Is ANK2 p.Ala41Thr (c.121G>A) pathogenic?

ANK2 p.Ala41Thr (c.121G>A) is classified Uncertain significance in ANK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-14). AlphaMissense: likely pathogenic (0.5978); Very rare (popmax 0.00223%, eas); Associated with ANK2-related disorder.

What condition is associated with ANK2 p.Ala41Thr (c.121G>A)?

ANK2 p.Ala41Thr (c.121G>A) is associated with ANK2-related disorder (ClinVar).

How common is ANK2 p.Ala41Thr (c.121G>A) in the general population?

ANK2 p.Ala41Thr (c.121G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ANK2 p.Ala41Thr (c.121G>A)?

AlphaMissense predicts likely pathogenic (score 0.5978) — an in-silico prediction, not a clinical call.

ANK2 p.Ala41Thr

c.121G>A · rs1085307623 · VCV426438

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

ANK2-related disorder

Computational evidence

Protein change
AlphaMissense	0.5978	likely pathogenic
REVEL	0.274	benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.55, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 183 kb · p 0.11 · regional, not allelic
Overall
CADD	28.0	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 0.00223% East Asian · 1/44,860 alleles

Overall 0.000124% 2/1,613,182 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,860
Admixed American	0.00167%	59,982

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.Ala41Thr
Coding: c.121G>A
MANE Select: NM_001148
dbSNP: rs1085307623
Type: single nucleotide variant
Location: chr4:113174452 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 41: an α-helix

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

Disease context

ANK2-related disorder

Similar variants

ANK2 p.Ala41Gly Uncertain significance ★★ 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.Gln2672His Uncertain significance ★★ ⚠ same condition
ANK2 p.Lys114Glu Uncertain significance ★★ same condition
ANK2 c.10682-2A>G Likely pathogenic ★ 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-ala41thr (accessed [today's date]).

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