Is ANKLE2 p.His671Tyr (c.2011C>T) pathogenic?

ANKLE2 p.His671Tyr (c.2011C>T) is classified Likely benign in ANKLE2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-09-11). AlphaMissense: likely benign (0.0747); Rare (popmax 0.156%, afr); Associated with ANKLE2-related disorder.

What condition is associated with ANKLE2 p.His671Tyr (c.2011C>T)?

ANKLE2 p.His671Tyr (c.2011C>T) is associated with ANKLE2-related disorder (ClinVar).

How common is ANKLE2 p.His671Tyr (c.2011C>T) in the general population?

ANKLE2 p.His671Tyr (c.2011C>T) is rare (popmax 0.156%, afr) (gnomAD).

What do computational predictors say about ANKLE2 p.His671Tyr (c.2011C>T)?

AlphaMissense predicts likely benign (score 0.0747) — an in-silico prediction, not a clinical call.

ANKLE2 p.His671Tyr

c.2011C>T · rs376393173 · VCV3054584

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0747 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.156%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ANKLE2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0747	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -6.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.39
Regional constraint	o/e 1.04	unconstrained · MANE · 21 kb · p 0.32 · regional, not allelic
Overall
CADD	6.869	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 0.156% African / African-American · 117/75,026 alleles

Filtering AF 0.133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.124%

Overall 0.00831% 134/1,611,900 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.156%	641
Admixed American	0.0167%	5,995
Remaining individualsnot grpmax-eligible	0.0112%	8,918

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.His671Tyr
Coding: c.2011C>T
MANE Select: NM_015114
dbSNP: rs376393173
Type: single nucleotide variant
Location: chr12:132730151 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14
Residue 671: a UniProt-annotated variant site (in mcph16; uncertain significance)

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

Disease context

ANKLE2-related disorder

Similar variants

ANKLE2 c.*8G>A Likely benign same condition
ANKLE2 p.Ala712= Likely benign same condition
ANKLE2 p.Gly700= Likely benign same condition
ANKLE2 p.Pro664= Likely benign same condition
ANKLE2 p.Pro910= Likely benign same condition
ANKLE2 c.1892-11_1892-9del Likely benign same condition
ANKLE2 p.Arg624Ter Pathogenic ★★ same type
ANKLE2 p.Arg99Ser 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-his671tyr (accessed [today's date]).

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