Is ANK1 p.Leu1483Arg (c.4448T>G) pathogenic?

ANK1 p.Leu1483Arg (c.4448T>G) is classified Conflicting classifications of pathogenicity in ANK1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-01). AlphaMissense: ambiguous (0.4674); Rare (popmax 0.198%, amr); Associated with hereditary spherocytosis type 1.

What condition is associated with ANK1 p.Leu1483Arg (c.4448T>G)?

ANK1 p.Leu1483Arg (c.4448T>G) is associated with hereditary spherocytosis type 1 (ClinVar).

How common is ANK1 p.Leu1483Arg (c.4448T>G) in the general population?

ANK1 p.Leu1483Arg (c.4448T>G) is rare (popmax 0.198%, amr) (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.Leu1483Arg (c.4448T>G)?

AlphaMissense predicts ambiguous (score 0.4674) — an in-silico prediction, not a clinical call.

ANK1 p.Leu1483Arg

c.4448T>G · rs141408004 · VCV747995

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4674 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.198%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary spherocytosis type 1

Computational evidence

Protein change
AlphaMissense	0.4674	ambiguous
REVEL	0.877	moderately pathogenic-leaning
SaProt	LLR -13.55	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 23 kb · p 0.11 · regional, not allelic
Overall
CADD	23.8	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 0.198% Admixed American · 119/60,020 alleles

Filtering AF 0.169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.158%

Overall 0.0438% 707/1,613,902 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.198%	504
Remaining individualsnot grpmax-eligible	0.0496%	2,016
European (non-Finnish)	0.0462%	2,165
African / African-American	0.00933%	10,719
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
South Asian	0.00329%	30,352
Finnishnot grpmax-eligible	0.00157%	63,820

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.Leu1483Arg
Coding: c.4448T>G
MANE Select: NM_000037
dbSNP: rs141408004
Type: single nucleotide variant
Location: chr8:41684633 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.64 · 21 PDB
Residue 1483: 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.Leu1483Met 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
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-leu1483arg (accessed [today's date]).

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