Is ANK2 p.Val77Met (c.229G>A) pathogenic?

ANK2 p.Val77Met (c.229G>A) is classified Conflicting classifications of pathogenicity in ANK2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-02). AlphaMissense: likely benign (0.1396); Very rare (popmax 0.00331%, nfe); Associated with cardiac arrhythmia, ankyrin-B-related.

What condition is associated with ANK2 p.Val77Met (c.229G>A)?

ANK2 p.Val77Met (c.229G>A) is associated with cardiac arrhythmia, ankyrin-B-related, long QT syndrome (ClinVar).

How common is ANK2 p.Val77Met (c.229G>A) in the general population?

ANK2 p.Val77Met (c.229G>A) is very rare (popmax 0.00331%, nfe) (gnomAD).

How is Romano-Ward syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ANK2 p.Val77Met (c.229G>A)?

AlphaMissense predicts likely benign (score 0.1396) — an in-silico prediction, not a clinical call.

ANK2 p.Val77Met

c.229G>A · rs776254819 · VCV1010772

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1396 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, nfe)

Conditions

cardiac arrhythmia, ankyrin-B-related

Computational evidence

Protein change
AlphaMissense	0.1396	likely benign
REVEL	0.318	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 183 kb · p 0.11 · regional, not allelic
Overall
CADD	27.2	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 0.00331% European (non-Finnish) · 39/1,179,980 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00242% 39/1,613,848 alleles · very rare exomes 31/1,461,518 · genomes 8/152,330 · joint denominator

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.Val77Met
Coding: c.229G>A
MANE Select: NM_001148
dbSNP: rs776254819
Type: single nucleotide variant
Location: chr4:113196410 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 77: an α-helix

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

Disease context

cardiac arrhythmia, ankyrin-B-related — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: long QT syndrome

For Romano-Ward syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ANK2 p.Val77= Conflicting classifications of pathogenicity ★ 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-val77met (accessed [today's date]).

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