Is ANK2 p.Val47Phe (c.139G>T) pathogenic?

ANK2 p.Val47Phe (c.139G>T) is classified Uncertain significance in ANK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-18). AlphaMissense: likely pathogenic (0.9662); Very rare (popmax 0.000254%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with ANK2 p.Val47Phe (c.139G>T)?

ANK2 p.Val47Phe (c.139G>T) is associated with Cardiovascular phenotype, long QT syndrome (ClinVar).

How common is ANK2 p.Val47Phe (c.139G>T) in the general population?

ANK2 p.Val47Phe (c.139G>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ANK2 p.Val47Phe (c.139G>T)?

AlphaMissense predicts likely pathogenic (score 0.9662) — an in-silico prediction, not a clinical call.

ANK2 p.Val47Phe

c.139G>T · rs1388701783 · VCV457021

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9662 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9662	likely pathogenic
REVEL	0.75	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; 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 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 183 kb · p 0.11 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000254% European (non-Finnish) · 3/1,179,554 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000992% 16/1,613,222 alleles · very rare exomes 14/1,461,012 · genomes 2/152,210 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0406%	2,464
Remaining individualsnot grpmax-eligible	0.0016%	62,440
European (non-Finnish)grpmax	0.000254%	393,185

Ashkenazi Jewish 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.Val47Phe
Coding: c.139G>T
MANE Select: NM_001148
dbSNP: rs1388701783
Type: single nucleotide variant
Location: chr4:113174470 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 47: an α-helix

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: long QT syndrome

Similar variants

ANK2 p.Val47Ala Uncertain significance ★ same residue
ANK2 p.Val47Leu Uncertain significance ★ same residue
ANK2 p.Arg3113Ter Pathogenic ★★ same condition
ANK2 p.Arg895Ter Pathogenic/Likely pathogenic ★★ same condition
ANK2 p.Arg977Ter 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

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-val47phe (accessed [today's date]).

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