Is ANK1 p.Leu163Pro (c.488T>C) pathogenic?

ANK1 p.Leu163Pro (c.488T>C) is classified Uncertain significance in ANK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-01). AlphaMissense: likely pathogenic (0.9999); Very rare (popmax 8.48e-05%, nfe).

How common is ANK1 p.Leu163Pro (c.488T>C) in the general population?

ANK1 p.Leu163Pro (c.488T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ANK1 p.Leu163Pro (c.488T>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

ANK1 p.Leu163Pro

c.488T>C · rs2150659130 · VCV1163303

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 1% in ANK1
REVEL	0.928	moderately pathogenic-leaning
SaProt	LLR -17.58	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,930 alleles

Overall 6.84e-05% 1/1,461,198 alleles · very rare

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.Leu163Pro
Coding: c.488T>C
MANE Select: NM_000037
dbSNP: rs2150659130
Type: single nucleotide variant
Location: chr8:41725885 (GRCh38)
Gene constraint: LOEUF 0.299 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.64 · 21 PDB
Residue 163: an α-helix; the '89 kda domain' region

Full ANK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANK1 p.Leu163= Benign/Likely benign ★★ same residue
ANK1 p.Leu163Phe Uncertain significance ★ ⚠ same residue
ANK1 c.1305+1G>A Pathogenic ★★ same type
ANK1 c.1405-9G>A Pathogenic/Likely pathogenic ★★ same type
ANK1 c.1702-2A>G Pathogenic/Likely pathogenic ★★ same type
ANK1 c.1801-17G>A Pathogenic/Likely pathogenic ★★ same type
ANK1 c.1801-2A>T Likely pathogenic ★★ same type
ANK1 c.1998+1G>T Likely pathogenic ★★ same type

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-leu163pro (accessed [today's date]).

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