Is ANK2 p.Asn1638Asp (c.4912A>G) pathogenic?

ANK2 p.Asn1638Asp (c.4912A>G) is classified Conflicting classifications of pathogenicity in ANK2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-09). AlphaMissense: likely benign (0.0755); Ultra-rare (popmax 0.015%, amr); Associated with long QT syndrome.

What condition is associated with ANK2 p.Asn1638Asp (c.4912A>G)?

ANK2 p.Asn1638Asp (c.4912A>G) is associated with long QT syndrome (ClinVar).

How common is ANK2 p.Asn1638Asp (c.4912A>G) in the general population?

ANK2 p.Asn1638Asp (c.4912A>G) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about ANK2 p.Asn1638Asp (c.4912A>G)?

AlphaMissense predicts likely benign (score 0.0755) — an in-silico prediction, not a clinical call.

ANK2 p.Asn1638Asp

c.4912A>G · rs748573794 · VCV632634

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0755 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

long QT syndrome

Computational evidence

Protein change
AlphaMissense	0.0755	likely benign
REVEL	0.104	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 0.29, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 98 kb · p 4.4e-21 · regional, not allelic
Overall
CADD	13.75	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

Grpmax group 0.015% Admixed American · 9/60,000 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.000929% 15/1,613,948 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,667
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00133%	74,912
European (non-Finnish)	0.000254%	393,317

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.Asn1638Asp
Coding: c.4912A>G
MANE Select: NM_001148
dbSNP: rs748573794
Type: single nucleotide variant
Location: chr4:113353530 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

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-asn1638asp (accessed [today's date]).

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