Is ANK2 p.Ser646Phe (c.1937C>T) pathogenic?

ANK2 p.Ser646Phe (c.1937C>T) is classified Conflicting classifications of pathogenicity in ANK2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-30). AlphaMissense: likely benign (0.1713); Absent from gnomAD v4.1; Associated with ANK2-related disorder.

What condition is associated with ANK2 p.Ser646Phe (c.1937C>T)?

ANK2 p.Ser646Phe (c.1937C>T) is associated with ANK2-related disorder (ClinVar).

How common is ANK2 p.Ser646Phe (c.1937C>T) in the general population?

ANK2 p.Ser646Phe (c.1937C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ANK2 p.Ser646Phe (c.1937C>T)?

AlphaMissense predicts likely benign (score 0.1713) — an in-silico prediction, not a clinical call.

ANK2 p.Ser646Phe

c.1937C>T · rs786205724 · VCV190552

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1713 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

ANK2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1713	likely benign
REVEL	0.304	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.72, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 98 kb · p 4.4e-21 · regional, not allelic
Overall
CADD	25.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ANK2
Protein: p.Ser646Phe
Coding: c.1937C>T
MANE Select: NM_001148
dbSNP: rs786205724
Type: single nucleotide variant
Location: chr4:113282730 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 646: an α-helix

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

Disease context

ANK2-related disorder

Similar variants

ANK2 p.Arg1088Ter Pathogenic ★★ same condition
ANK2 p.Arg888Ter Pathogenic/Likely pathogenic ★★ same condition
ANK2 c.85-28508A>G Uncertain significance ★★ same condition
ANK2 c.85-57022A>C Uncertain significance ★★ same condition
ANK2 p.Ala41Thr Uncertain significance ★★ ⚠ same condition
ANK2 p.Gln2672His Uncertain significance ★★ ⚠ same condition
ANK2 p.Lys114Glu Uncertain significance ★★ same condition
ANK2 c.10682-2A>G Likely pathogenic ★ 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-ser646phe (accessed [today's date]).

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