Is ANK2 p.Ser2997Pro (c.8989T>C) pathogenic?

ANK2 p.Ser2997Pro (c.8989T>C) is classified Uncertain significance in ANK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-19). AlphaMissense: likely benign (0.0736); Very rare (popmax 0.00267%, afr); Associated with long QT syndrome.

What condition is associated with ANK2 p.Ser2997Pro (c.8989T>C)?

ANK2 p.Ser2997Pro (c.8989T>C) is associated with long QT syndrome (ClinVar).

How common is ANK2 p.Ser2997Pro (c.8989T>C) in the general population?

ANK2 p.Ser2997Pro (c.8989T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ANK2 p.Ser2997Pro (c.8989T>C)?

AlphaMissense predicts likely benign (score 0.0736) — an in-silico prediction, not a clinical call.

ANK2 p.Ser2997Pro

c.8989T>C · rs1213001504 · VCV1008742

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0736 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

long QT syndrome

Computational evidence

Protein change
AlphaMissense	0.0736	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.17	GERP -4.8, phastCons 0.007
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.16 · regional, not allelic
Overall
CADD	6.235	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,916 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000867% 14/1,614,010 alleles · very rare exomes 11/1,461,834 · genomes 3/152,176 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,458
Remaining individualsnot grpmax-eligible	0.0016%	62,486
Finnishnot grpmax-eligible	0.00156%	64,030
European (non-Finnish)	0.000847%	118,000

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.Ser2997Pro
Coding: c.8989T>C
MANE Select: NM_001148
dbSNP: rs1213001504
Type: single nucleotide variant
Location: chr4:113357607 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2997: 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.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
ANK2 c.85-3C>T 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-ser2997pro (accessed [today's date]).

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