Is ANK2 p.Leu947Pro (c.2840T>C) pathogenic?

ANK2 p.Leu947Pro (c.2840T>C) is classified Uncertain significance in ANK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-01). AlphaMissense: likely pathogenic (0.6257); Very rare (popmax 8.48e-05%, nfe).

How common is ANK2 p.Leu947Pro (c.2840T>C) in the general population?

ANK2 p.Leu947Pro (c.2840T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ANK2 p.Leu947Pro (c.2840T>C)?

AlphaMissense predicts likely pathogenic (score 0.6257) — an in-silico prediction, not a clinical call.

ANK2 p.Leu947Pro

c.2840T>C · rs786205734 · VCV190599

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6257 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.6257	likely pathogenic
REVEL	0.698	pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 98 kb · p 4.4e-21 · regional, not allelic
Overall
CADD	26.1	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) · 1/1,179,830 alleles

Overall 6.84e-05% 1/1,461,536 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: ANK2
Protein: p.Leu947Pro
Coding: c.2840T>C
MANE Select: NM_001148
dbSNP: rs786205734
Type: single nucleotide variant
Location: chr4:113318560 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

Full ANK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANK2 p.Leu947= Likely benign ★★ same residue
ANK2 p.Arg1007Ter Pathogenic/Likely pathogenic ★★ same type
ANK2 p.Arg1088Ter Pathogenic ★★ same type
ANK2 p.Arg3113Ter Pathogenic ★★ same type
ANK2 p.Arg888Ter Pathogenic/Likely pathogenic ★★ same type
ANK2 p.Arg895Ter Pathogenic/Likely pathogenic ★★ same type
ANK2 p.Arg977Ter Pathogenic ★★ same type
ANK2 c.11032+11G>T Uncertain significance ★★ 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/ank2-p-leu947pro (accessed [today's date]).

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