Is ANK1 p.Leu971= (c.2913G>C) pathogenic?

ANK1 p.Leu971= (c.2913G>C) is classified Benign/Likely benign in ANK1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-03). Common (popmax 56.9%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Spherocytosis.

What condition is associated with ANK1 p.Leu971= (c.2913G>C)?

ANK1 p.Leu971= (c.2913G>C) is associated with Spherocytosis, hereditary spherocytosis type 1 (ClinVar).

ANK1 p.Leu971=

Q: How common is ANK1 p.Leu971= (c.2913G>C) in the general population?

ANK1 p.Leu971= (c.2913G>C) is common (popmax 56.9%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2913G>C · rs504574 · VCV261301

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 56.9%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

Spherocytosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.212	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.51	GERP -1.2, phastCons 0.026
Overall
CADD	6.603	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 56.9% Admixed American · 34,120/60,006 alleles

Filtering AF 56.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 56.1%

Overall 46.3% 747,048/1,613,058 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	57.3%	2
Admixed Americangrpmax	56.9%	2
Finnishnot grpmax-eligible	55.9%	2
East Asian	52.5%	2
South Asian	50.6%	2
European (non-Finnish)	46.9%	2
Remaining individualsnot grpmax-eligible	46.3%	2
Ashkenazi Jewishnot grpmax-eligible	42.9%	2
Middle Eastern	41.1%	2
African / African-American	13.7%	7

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu971=
Coding: c.2913G>C
MANE Select: NM_000037
dbSNP: rs504574
Type: single nucleotide variant
Location: chr8:41696410 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.64 · 21 PDB
Residue 971: a β-strand; the zu5 1 domain

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.Leu971Gln 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-leu971 (accessed [today's date]).

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