Is ANK1 p.Val1223Ala (c.3668T>C) pathogenic?

ANK1 p.Val1223Ala (c.3668T>C) is classified Conflicting classifications of pathogenicity in ANK1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-25). AlphaMissense: ambiguous (0.4122); Rare (popmax 0.822%, eas); Associated with hereditary spherocytosis type 1.

What condition is associated with ANK1 p.Val1223Ala (c.3668T>C)?

ANK1 p.Val1223Ala (c.3668T>C) is associated with hereditary spherocytosis type 1 (ClinVar).

How common is ANK1 p.Val1223Ala (c.3668T>C) in the general population?

ANK1 p.Val1223Ala (c.3668T>C) is rare (popmax 0.822%, eas) (gnomAD).

How is Hereditary spherocytosis inherited?

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

What do computational predictors say about ANK1 p.Val1223Ala (c.3668T>C)?

AlphaMissense predicts ambiguous (score 0.4122) — an in-silico prediction, not a clinical call.

ANK1 p.Val1223Ala

c.3668T>C · rs185516533 · VCV708038

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4122 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.822%, eas)

Conditions

hereditary spherocytosis type 1

Computational evidence

Protein change
AlphaMissense	0.4122	ambiguous
REVEL	0.416	indeterminate
SaProt	LLR -7.74	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 38 kb · p 1e-12 · regional, not allelic
Overall
CADD	24.6	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 0.822% East Asian · 369/44,870 alleles

Filtering AF 0.753% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.726%

Overall 0.0291% 469/1,614,122 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.822%	122
South Asian	0.0867%	1,153
Remaining individualsnot grpmax-eligible	0.032%	3,126
European (non-Finnish)	8.47e-05%	1,180,038

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.Val1223Ala
Coding: c.3668T>C
MANE Select: NM_000037
dbSNP: rs185516533
Type: single nucleotide variant
Location: chr8:41692838 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.64 · 21 PDB
Residue 1223: an α-helix

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-val1223ala (accessed [today's date]).

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