Is ANK2 p.Phe2883Val (c.8647T>G) pathogenic?

ANK2 p.Phe2883Val (c.8647T>G) is classified Conflicting classifications of pathogenicity in ANK2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-28). AlphaMissense: likely benign (0.0638); Very rare (popmax 0.00439%, sas); Associated with long QT syndrome.

What condition is associated with ANK2 p.Phe2883Val (c.8647T>G)?

ANK2 p.Phe2883Val (c.8647T>G) is associated with long QT syndrome, cardiac arrhythmia, ankyrin-B-related (ClinVar).

How common is ANK2 p.Phe2883Val (c.8647T>G) in the general population?

ANK2 p.Phe2883Val (c.8647T>G) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about ANK2 p.Phe2883Val (c.8647T>G)?

AlphaMissense predicts likely benign (score 0.0638) — an in-silico prediction, not a clinical call.

ANK2 p.Phe2883Val

c.8647T>G · rs778307564 · VCV519530

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0638 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

long QT syndrome

Computational evidence

Protein change
AlphaMissense	0.0638	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.029	GERP -3.8
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.16 · regional, not allelic
Overall
CADD	9.723	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,088 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.0039% 63/1,613,918 alleles · very rare exomes 57/1,461,766 · genomes 6/152,152 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0109%	9,137
South Asiangrpmax	0.00439%	22,772
European (non-Finnish)	0.00424%	23,600
Remaining individualsnot grpmax-eligible	0.0032%	31,241

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe2883Val
Coding: c.8647T>G
MANE Select: NM_001148
dbSNP: rs778307564
Type: single nucleotide variant
Location: chr4:113357265 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2883: 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

Also linked: cardiac arrhythmia, ankyrin-B-related

Similar variants

ANK2 p.Phe2883Ser Uncertain significance ★ ⚠ same residue
ANK2 p.Arg1007Ter Pathogenic/Likely pathogenic ★★ same condition
ANK2 p.Arg1088Ter Pathogenic ★★ same condition
ANK2 p.Arg3113Ter Pathogenic ★★ same condition
ANK2 c.11032+11G>T Uncertain significance ★★ 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

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-phe2883val (accessed [today's date]).

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