Is ANK1 p.Arg512Gly (c.1534C>G) pathogenic?

ANK1 p.Arg512Gly (c.1534C>G) is classified Uncertain significance in ANK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: likely pathogenic (0.9255); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ANK1 p.Arg512Gly (c.1534C>G)?

ANK1 p.Arg512Gly (c.1534C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ANK1 p.Arg512Gly (c.1534C>G) in the general population?

ANK1 p.Arg512Gly (c.1534C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ANK1 p.Arg512Gly (c.1534C>G)?

AlphaMissense predicts likely pathogenic (score 0.9255) — an in-silico prediction, not a clinical call.

ANK1 p.Arg512Gly

c.1534C>G · VCV4050450

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9255 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9255	likely pathogenic
REVEL	0.51	indeterminate
SaProt	LLR -12.88	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.21	donor gain · deltas
Constraint at this position
Conservation	phyloP 7.5	GERP -1.2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 38 kb · p 1e-12 · regional, not allelic
Overall
CADD	24.0	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,030 alleles

Overall 6.84e-05% 1/1,461,848 alleles · very rare

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.Arg512Gly
Coding: c.1534C>G
MANE Select: NM_000037
Type: single nucleotide variant
Location: chr8:41715720 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.64 · 21 PDB
Residue 512: an α-helix; the '89 kda domain' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ANK1 p.Arg512Cys Uncertain significance ★★ ⚠ same residue
ANK1 p.Arg512His Uncertain significance ★ ⚠ same residue
ANK1 p.Ala1590Thr Uncertain significance ★★ ⚠ same condition
ANK1 p.Ala1659Val Uncertain significance ★★ ⚠ same condition
ANK1 p.Ala1789Thr Uncertain significance ★★ ⚠ same condition
ANK1 p.Ala329Ser Uncertain significance ★★ ⚠ same condition
ANK1 p.Ala543Val Uncertain significance ★★ ⚠ same condition
ANK1 p.Arg1148Gln 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/ank1-p-arg512gly (accessed [today's date]).

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