Is ANK1 p.Pro1096= (c.3288G>A) pathogenic?

ANK1 p.Pro1096= (c.3288G>A) is classified Conflicting classifications of pathogenicity in ANK1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-18). Ultra-rare (popmax 0.0362%, sas); Associated with hereditary spherocytosis type 1.

What condition is associated with ANK1 p.Pro1096= (c.3288G>A)?

ANK1 p.Pro1096= (c.3288G>A) is associated with hereditary spherocytosis type 1 (ClinVar).

How common is ANK1 p.Pro1096= (c.3288G>A) in the general population?

ANK1 p.Pro1096= (c.3288G>A) is ultra-rare (popmax 0.0362%, sas) (gnomAD).

How is Hereditary spherocytosis inherited?

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

ANK1 p.Pro1096=

c.3288G>A · rs140964621 · VCV363007

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0362%, sas)

Conditions

hereditary spherocytosis type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.066	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -4.3
Overall
CADD	0.156	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0362% South Asian · 33/91,078 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0231%

Overall 0.0211% 341/1,614,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0362%	2,760
European (non-Finnish)	0.0236%	4,229
Admixed American	0.0133%	7,502
Remaining individualsnot grpmax-eligible	0.0128%	7,812
African / African-American	0.0107%	9,379
East Asian	0.00891%	11,220
Finnishnot grpmax-eligible	0.00156%	63,948

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.Pro1096=
Coding: c.3288G>A
MANE Select: NM_000037
dbSNP: rs140964621
Type: single nucleotide variant
Location: chr8:41694631 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.64 · 21 PDB
Residue 1096: the zu5 2 domain

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 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
ANK1 c.2389-2A>G Likely pathogenic ★★ same condition
ANK1 c.2462-2A>G 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-pro1096 (accessed [today's date]).

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