Is ANK1 p.Arg512His (c.1535G>A) pathogenic?

ANK1 p.Arg512His (c.1535G>A) is classified Uncertain significance in ANK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely pathogenic (0.7558); Ultra-rare (popmax 0.0747%, sas); Associated with Spherocytosis.

What condition is associated with ANK1 p.Arg512His (c.1535G>A)?

ANK1 p.Arg512His (c.1535G>A) is associated with Spherocytosis, hereditary spherocytosis type 1 (ClinVar).

How common is ANK1 p.Arg512His (c.1535G>A) in the general population?

ANK1 p.Arg512His (c.1535G>A) is ultra-rare (popmax 0.0747%, sas) (gnomAD).

What do computational predictors say about ANK1 p.Arg512His (c.1535G>A)?

AlphaMissense predicts likely pathogenic (score 0.7558) — an in-silico prediction, not a clinical call.

ANK1 p.Arg512His

c.1535G>A · rs371259018 · VCV908159

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7558 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0747%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Spherocytosis

Computational evidence

Protein change
AlphaMissense	0.7558	likely pathogenic
REVEL	0.418	indeterminate
SaProt	LLR -9.88	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 38 kb · p 1e-12 · regional, not allelic
Overall
CADD	24.3	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 0.0747% South Asian · 68/91,070 alleles

Filtering AF 0.0604% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0552%

Overall 0.00936% 151/1,614,108 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0747%	1,339
Middle Eastern	0.0498%	2,009
Remaining individualsnot grpmax-eligible	0.0288%	3,473
Admixed American	0.02%	5,003
African / African-American	0.008%	12,507
East Asian	0.00668%	14,961
European (non-Finnish)	0.00339%	29,501
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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.Arg512His
Coding: c.1535G>A
MANE Select: NM_000037
dbSNP: rs371259018
Type: single nucleotide variant
Location: chr8:41715719 (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

Spherocytosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spherocytosis type 1

Similar variants

ANK1 p.Arg512Cys 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-arg512his (accessed [today's date]).

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