Is ANK2 p.Pro599Ser (c.1795C>T) pathogenic?

ANK2 p.Pro599Ser (c.1795C>T) is classified Uncertain significance in ANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-19). AlphaMissense: ambiguous (0.4343); Very rare (popmax 0.00223%, eas); Associated with long QT syndrome.

What condition is associated with ANK2 p.Pro599Ser (c.1795C>T)?

ANK2 p.Pro599Ser (c.1795C>T) is associated with long QT syndrome (ClinVar).

How common is ANK2 p.Pro599Ser (c.1795C>T) in the general population?

ANK2 p.Pro599Ser (c.1795C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ANK2 p.Pro599Ser (c.1795C>T)?

AlphaMissense predicts ambiguous (score 0.4343) — an in-silico prediction, not a clinical call.

ANK2 p.Pro599Ser

c.1795C>T · VCV3689932

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4343 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

long QT syndrome

Computational evidence

Protein change
AlphaMissense	0.4343	ambiguous
REVEL	0.669	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 98 kb · p 4.4e-21 · regional, not allelic
Overall
CADD	26.6	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 · 1/44,872 alleles

Overall 0.000658% 1/152,074 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.Pro599Ser
Coding: c.1795C>T
MANE Select: NM_001148
Type: single nucleotide variant
Location: chr4:113278472 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 599: an α-helix

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

Disease context

long QT syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ANK2 p.Pro599= Likely benign ★ same residue
ANK2 p.Arg3113Ter Pathogenic ★★ same condition
ANK2 c.11611-3T>A Uncertain significance ★★ same condition
ANK2 c.1783-3C>T Uncertain significance ★★ same condition
ANK2 c.2079+5T>G Uncertain significance ★★ same condition
ANK2 c.2278-3C>T Uncertain significance ★★ same condition
ANK2 c.3125+6G>A Uncertain significance ★★ same condition
ANK2 c.693+6G>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-pro599ser (accessed [today's date]).

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