Is ANKLE2 p.Arg746Cys (c.2236C>T) pathogenic?

ANKLE2 p.Arg746Cys (c.2236C>T) is classified Uncertain significance in ANKLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-13). AlphaMissense: likely benign (0.0693); Ultra-rare (popmax 0.0383%, amr); Associated with Inborn genetic diseases.

What condition is associated with ANKLE2 p.Arg746Cys (c.2236C>T)?

ANKLE2 p.Arg746Cys (c.2236C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ANKLE2 p.Arg746Cys (c.2236C>T) in the general population?

ANKLE2 p.Arg746Cys (c.2236C>T) is ultra-rare (popmax 0.0383%, amr) (gnomAD).

What do computational predictors say about ANKLE2 p.Arg746Cys (c.2236C>T)?

AlphaMissense predicts likely benign (score 0.0693) — an in-silico prediction, not a clinical call.

ANKLE2 p.Arg746Cys

c.2236C>T · rs371204974 · VCV3121630

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0693 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0383%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0693	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -7.56	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 0.1
Regional constraint	o/e 1.04	unconstrained · MANE · 21 kb · p 0.32 · regional, not allelic
Overall
CADD	17.82	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0383% Admixed American · 23/59,988 alleles

Filtering AF 0.0302% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0291%

Overall 0.0263% 424/1,613,476 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0383%	2,608
European (non-Finnish)	0.0329%	3,041
Middle Eastern	0.0164%	6,082
Remaining individualsnot grpmax-eligible	0.008%	12,495
African / African-American	0.00668%	14,971
South Asian	0.0022%	45,539

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.Arg746Cys
Coding: c.2236C>T
MANE Select: NM_015114
dbSNP: rs371204974
Type: single nucleotide variant
Location: chr12:132729926 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14
Residue 746: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ANKLE2 p.Arg99Ser Uncertain significance ★★ ⚠ same condition
ANKLE2 p.Asn633His Uncertain significance ★★ ⚠ same condition
ANKLE2 p.Asn660Ile Uncertain significance ★★ ⚠ same condition
ANKLE2 p.His893Tyr Uncertain significance ★★ ⚠ same condition
ANKLE2 p.Lys473Arg Uncertain significance ★★ ⚠ same condition
ANKLE2 p.Phe549Val Uncertain significance ★★ ⚠ same condition
ANKLE2 p.Pro377Leu Uncertain significance ★★ ⚠ same condition
ANKLE2 p.Pro37Arg Uncertain significance ★★ ⚠ 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/ankle2-p-arg746cys (accessed [today's date]).

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