Is ANKLE2 p.Arg33Trp (c.97C>T) pathogenic?

ANKLE2 p.Arg33Trp (c.97C>T) is classified Uncertain significance in ANKLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-12). AlphaMissense: ambiguous (0.3524); Very rare (popmax 0.00269%, amr); Associated with Inborn genetic diseases.

What condition is associated with ANKLE2 p.Arg33Trp (c.97C>T)?

ANKLE2 p.Arg33Trp (c.97C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ANKLE2 p.Arg33Trp (c.97C>T) in the general population?

ANKLE2 p.Arg33Trp (c.97C>T) is very rare (popmax 0.00269%, amr) (gnomAD).

What do computational predictors say about ANKLE2 p.Arg33Trp (c.97C>T)?

AlphaMissense predicts ambiguous (score 0.3524) — an in-silico prediction, not a clinical call.

ANKLE2 p.Arg33Trp

c.97C>T · VCV3865750

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3524 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00269%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3524	ambiguous
REVEL	0.263	benign-leaning
SaProt	LLR -9.04	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 0.85, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 14 kb · p 0.17 · regional, not allelic
Overall
CADD	24.7	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 0.00269% Admixed American · 1/37,242 alleles

Overall 0.00025% 3/1,198,254 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00269%	37,242
South Asian	0.0017%	58,690
European (non-Finnish)	9.59e-05%	1,042,685

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.Arg33Trp
Coding: c.97C>T
MANE Select: NM_015114
Type: single nucleotide variant
Location: chr12:132761702 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14

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-arg33trp (accessed [today's date]).

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