Is ANK1 p.Ala399= (c.1197G>A) pathogenic?

ANK1 p.Ala399= (c.1197G>A) is classified Conflicting classifications of pathogenicity in ANK1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-11-11). Ultra-rare (popmax 0.0217%, amr); Associated with Spherocytosis.

What condition is associated with ANK1 p.Ala399= (c.1197G>A)?

ANK1 p.Ala399= (c.1197G>A) is associated with Spherocytosis, hereditary spherocytosis type 1 (ClinVar).

How common is ANK1 p.Ala399= (c.1197G>A) in the general population?

ANK1 p.Ala399= (c.1197G>A) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

ANK1 p.Ala399=

c.1197G>A · rs756075877 · VCV908233

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Conditions

Spherocytosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -4.3
Overall
CADD	0.217	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0217% Admixed American · 13/59,996 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00384% 62/1,613,754 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,615
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)	0.00339%	29,499
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
South Asian	0.00329%	30,359
East Asian	0.00223%	44,892
African / African-American	0.00133%	74,914

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.Ala399=
Coding: c.1197G>A
MANE Select: NM_000037
dbSNP: rs756075877
Type: single nucleotide variant
Location: chr8:41718115 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.64 · 21 PDB
Residue 399: 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.Ala399fs Likely pathogenic ★ same residue
ANK1 p.Ala399Thr Uncertain significance ★ ⚠ same residue
ANK1 p.Ala399Val 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

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-ala399 (accessed [today's date]).

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