Is ANK1 p.Glu840Lys (c.2518G>A) pathogenic?

ANK1 p.Glu840Lys (c.2518G>A) is classified Uncertain significance in ANK1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-04). AlphaMissense: likely benign (0.1096); Ultra-rare (popmax 0.0285%, sas).

How common is ANK1 p.Glu840Lys (c.2518G>A) in the general population?

ANK1 p.Glu840Lys (c.2518G>A) is ultra-rare (popmax 0.0285%, sas) (gnomAD).

What do computational predictors say about ANK1 p.Glu840Lys (c.2518G>A)?

AlphaMissense predicts likely benign (score 0.1096) — an in-silico prediction, not a clinical call.

ANK1 p.Glu840Lys

c.2518G>A · rs746374514 · VCV1693982

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1096 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0285%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1096	likely benign
REVEL	0.278	benign-leaning
SaProt	LLR -7.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 38 kb · p 1e-12 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0285% South Asian · 26/91,078 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0171%

Overall 0.00205% 30/1,461,828 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0285%	3,503
Remaining individualsnot grpmax-eligible	0.0032%	31,255
European (non-Finnish)	0.000169%	590,019

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: ANK1
Protein: p.Glu840Lys
Coding: c.2518G>A
MANE Select: NM_000037
dbSNP: rs746374514
Type: single nucleotide variant
Location: chr8:41699492 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.64 · 21 PDB

Full ANK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANK1 p.Glu840= Likely benign ★ same residue
ANK1 c.1305+1G>A Pathogenic ★★ same type
ANK1 c.1405-9G>A Pathogenic/Likely pathogenic ★★ same type
ANK1 c.1702-2A>G Pathogenic/Likely pathogenic ★★ same type
ANK1 c.1801-17G>A Pathogenic/Likely pathogenic ★★ same type
ANK1 c.1801-2A>T Likely pathogenic ★★ same type
ANK1 c.1998+1G>T Likely pathogenic ★★ same type
ANK1 c.2296-1G>A Likely pathogenic ★★ same type

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/ank1-p-glu840lys (accessed [today's date]).

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