Is ANKLE2 p.His856= (c.2568C>T) pathogenic?

ANKLE2 p.His856= (c.2568C>T) is classified Likely benign in ANKLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). Very rare (popmax 0.00017%, nfe).

How common is ANKLE2 p.His856= (c.2568C>T) in the general population?

ANKLE2 p.His856= (c.2568C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

ANKLE2 p.His856=

c.2568C>T · VCV4281448

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	phastCons 1
Overall
CADD	5.018	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,944 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,460,590 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: ANKLE2
Protein: p.His856=
Coding: c.2568C>T
MANE Select: NM_015114
Type: single nucleotide variant
Location: chr12:132728079 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14
Residue 856: a UniProt-annotated variant site (in mcph16; uncertain significance); a UniProt-annotated variant site (in mcph16)

Full ANKLE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKLE2 p.His856Arg Uncertain significance ★ ⚠ same residue
ANKLE2 p.Arg624Ter Pathogenic ★★ same type
ANKLE2 p.Arg99Ser Uncertain significance ★★ ⚠ same type
ANKLE2 p.Asn633His Uncertain significance ★★ ⚠ same type
ANKLE2 p.Asn660Ile Uncertain significance ★★ ⚠ same type
ANKLE2 p.His893Tyr Uncertain significance ★★ ⚠ same type
ANKLE2 p.Lys473Arg Uncertain significance ★★ ⚠ same type
ANKLE2 p.Phe549Val 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/ankle2-p-his856 (accessed [today's date]).

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