Is ANK2 p.Pro2796Leu (c.8387C>T) pathogenic?

ANK2 p.Pro2796Leu (c.8387C>T) is classified Conflicting classifications of pathogenicity in ANK2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-18). AlphaMissense: likely benign (0.0649); Ultra-rare (popmax 0.0223%, eas); Associated with long QT syndrome.

What condition is associated with ANK2 p.Pro2796Leu (c.8387C>T)?

ANK2 p.Pro2796Leu (c.8387C>T) is associated with long QT syndrome (ClinVar).

How common is ANK2 p.Pro2796Leu (c.8387C>T) in the general population?

ANK2 p.Pro2796Leu (c.8387C>T) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about ANK2 p.Pro2796Leu (c.8387C>T)?

AlphaMissense predicts likely benign (score 0.0649) — an in-silico prediction, not a clinical call.

ANK2 p.Pro2796Leu

c.8387C>T · rs182956726 · VCV519475

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0649 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

long QT syndrome

Computational evidence

Protein change
AlphaMissense	0.0649	likely benign
REVEL	0.045	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.91	GERP -5
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.16 · regional, not allelic
Overall
CADD	7.195	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 0.0223% East Asian · 10/44,850 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00917%

Overall 0.00235% 38/1,613,934 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,485
African / African-American	0.008%	12,498
Admixed American	0.00667%	15,001
Remaining individualsnot grpmax-eligible	0.0032%	31,250
European (non-Finnish)	0.00127%	78,664
South Asian	0.0011%	91,064

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.Pro2796Leu
Coding: c.8387C>T
MANE Select: NM_001148
dbSNP: rs182956726
Type: single nucleotide variant
Location: chr4:113357005 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2796: the 'disordered' region

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.Pro2796= Benign/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-pro2796leu (accessed [today's date]).

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