Is ANK2 p.Pro1240Ala (c.3718C>G) pathogenic?

ANK2 p.Pro1240Ala (c.3718C>G) is classified Uncertain significance in ANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-30). AlphaMissense: ambiguous (0.5495); Absent from gnomAD v4.1.

How common is ANK2 p.Pro1240Ala (c.3718C>G) in the general population?

ANK2 p.Pro1240Ala (c.3718C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ANK2 p.Pro1240Ala (c.3718C>G)?

AlphaMissense predicts ambiguous (score 0.5495) — an in-silico prediction, not a clinical call.

ANK2 p.Pro1240Ala

c.3718C>G · rs1057523529 · VCV389755

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5495 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.5495	ambiguous
REVEL	0.892	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 98 kb · p 4.4e-21 · regional, not allelic
Overall
CADD	25.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ANK2
Protein: p.Pro1240Ala
Coding: c.3718C>G
MANE Select: NM_001148
dbSNP: rs1057523529
Type: single nucleotide variant
Location: chr4:113336703 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1240: the zu5 2 domain; an α-helix

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

Similar variants

ANK2 p.Arg1007Ter Pathogenic/Likely pathogenic ★★ same type
ANK2 p.Arg1088Ter Pathogenic ★★ same type
ANK2 p.Arg3113Ter Pathogenic ★★ same type
ANK2 p.Arg888Ter Pathogenic/Likely pathogenic ★★ same type
ANK2 p.Arg895Ter Pathogenic/Likely pathogenic ★★ same type
ANK2 p.Arg977Ter Pathogenic ★★ same type
ANK2 c.11032+11G>T Uncertain significance ★★ same type
ANK2 c.11611-3T>A Uncertain significance ★★ 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-pro1240ala (accessed [today's date]).

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