Is ANK1 p.Arg512Cys (c.1534C>T) pathogenic?

ANK1 p.Arg512Cys (c.1534C>T) is classified Uncertain significance in ANK1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-26). AlphaMissense: likely pathogenic (0.8334); Very rare (popmax 0.00833%, amr); Associated with hereditary spherocytosis type 1.

What condition is associated with ANK1 p.Arg512Cys (c.1534C>T)?

ANK1 p.Arg512Cys (c.1534C>T) is associated with hereditary spherocytosis type 1 (ClinVar).

How common is ANK1 p.Arg512Cys (c.1534C>T) in the general population?

ANK1 p.Arg512Cys (c.1534C>T) is very rare (popmax 0.00833%, amr) (gnomAD).

How is Hereditary spherocytosis inherited?

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

What do computational predictors say about ANK1 p.Arg512Cys (c.1534C>T)?

AlphaMissense predicts likely pathogenic (score 0.8334) — an in-silico prediction, not a clinical call.

ANK1 p.Arg512Cys

c.1534C>T · VCV4077910

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8334 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary spherocytosis type 1

Computational evidence

Protein change
AlphaMissense	0.8334	likely pathogenic
REVEL	0.512	indeterminate
SaProt	LLR -12.88	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.21 · evaluated, not missing
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	24.4	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 0.00833% Admixed American · 5/60,030 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.00223% 36/1,614,140 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,006
East Asian	0.00446%	22,440
European (non-Finnish)	0.00237%	42,144
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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.Arg512Cys
Coding: c.1534C>T
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

hereditary spherocytosis type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary spherocytosis (Orphanet):

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

Similar variants

ANK1 p.Arg512His Uncertain significance ★ ⚠ same residue
ANK1 p.Arg512Gly Uncertain significance ★ ⚠ same residue
ANK1 c.1305+1G>A Pathogenic ★★ same condition
ANK1 c.1405-9G>A Pathogenic/Likely pathogenic ★★ same condition
ANK1 c.1702-2A>G Pathogenic/Likely pathogenic ★★ same condition
ANK1 c.1801-17G>A Pathogenic/Likely pathogenic ★★ same condition
ANK1 c.2296-1G>A Likely pathogenic ★★ same condition
ANK1 c.2296-2A>G Pathogenic/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/ank1-p-arg512cys (accessed [today's date]).

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