Is ANK1 p.Ser1447= (c.4341T>C) pathogenic?

ANK1 p.Ser1447= (c.4341T>C) is classified Conflicting classifications of pathogenicity in ANK1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-18). Ultra-rare (popmax 0.048%, afr); Associated with hereditary spherocytosis type 1.

What condition is associated with ANK1 p.Ser1447= (c.4341T>C)?

ANK1 p.Ser1447= (c.4341T>C) is associated with hereditary spherocytosis type 1 (ClinVar).

How common is ANK1 p.Ser1447= (c.4341T>C) in the general population?

ANK1 p.Ser1447= (c.4341T>C) is ultra-rare (popmax 0.048%, 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.Ser1447=

c.4341T>C · rs112677283 · VCV736985

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.048%, afr)

Conditions

hereditary spherocytosis type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.189	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4	GERP -3.6
Overall
CADD	1.523	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.048% African / African-American · 36/74,986 alleles

Filtering AF 0.0356% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.0039% 63/1,614,074 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.048%	2,083
Remaining individualsnot grpmax-eligible	0.0208%	4,808
Middle Eastern	0.0165%	6,058
Admixed American	0.00666%	15,006
South Asian	0.0022%	45,539
European (non-Finnish)	0.000593%	168,575

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.Ser1447=
Coding: c.4341T>C
MANE Select: NM_000037
dbSNP: rs112677283
Type: single nucleotide variant
Location: chr8:41686201 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.64 · 21 PDB
Residue 1447: an α-helix; the death domain; the '55 kda regulatory 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.Ser1447fs Pathogenic ★ 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
ANK1 c.2389-2A>G 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-ser1447 (accessed [today's date]).

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