Is ANK1 p.Leu489= (c.1467G>A) pathogenic?

ANK1 p.Leu489= (c.1467G>A) is classified Benign/Likely benign in ANK1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-17). Rare (popmax 0.236%, afr); Associated with hereditary spherocytosis type 1.

What condition is associated with ANK1 p.Leu489= (c.1467G>A)?

ANK1 p.Leu489= (c.1467G>A) is associated with hereditary spherocytosis type 1 (ClinVar).

How common is ANK1 p.Leu489= (c.1467G>A) in the general population?

ANK1 p.Leu489= (c.1467G>A) is rare (popmax 0.236%, afr) (gnomAD).

How is Hereditary spherocytosis inherited?

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

ANK1 p.Leu489=

c.1467G>A · rs148165519 · VCV711500

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.236%, afr)

Conditions

hereditary spherocytosis type 1

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 0.54	GERP -4.2, phastCons 1
Overall
CADD	6.617	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.236% African / African-American · 177/75,068 alleles

Filtering AF 0.207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.197%

Overall 0.0124% 200/1,614,238 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.236%	424
Remaining individualsnot grpmax-eligible	0.024%	4,167
Middle Eastern	0.0165%	6,058
South Asian	0.00439%	22,772
Admixed American	0.00167%	60,028
European (non-Finnish)	0.000169%	590,023

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.Leu489=
Coding: c.1467G>A
MANE Select: NM_000037
dbSNP: rs148165519
Type: single nucleotide variant
Location: chr8:41715787 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.64 · 21 PDB
Residue 489: 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 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-leu489 (accessed [today's date]).

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