Is ANKLE2 p.Tyr200Asp (c.598T>G) pathogenic?

ANKLE2 p.Tyr200Asp (c.598T>G) is classified Uncertain significance in ANKLE2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-25). AlphaMissense: likely pathogenic (0.9889); Very rare (popmax 0.00737%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ANKLE2 p.Tyr200Asp (c.598T>G)?

ANKLE2 p.Tyr200Asp (c.598T>G) is associated with Inborn genetic diseases (ClinVar).

How common is ANKLE2 p.Tyr200Asp (c.598T>G) in the general population?

ANKLE2 p.Tyr200Asp (c.598T>G) is very rare (popmax 0.00737%, nfe) (gnomAD).

What do computational predictors say about ANKLE2 p.Tyr200Asp (c.598T>G)?

AlphaMissense predicts likely pathogenic (score 0.9889) — an in-silico prediction, not a clinical call.

ANKLE2 p.Tyr200Asp

c.598T>G · VCV3370596

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9889 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00737%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9889	likely pathogenic · top 2% in ANKLE2
REVEL	0.705	pathogenic-leaning
SaProt	LLR -15.57	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 14 kb · p 0.17 · regional, not allelic
Overall
CADD	26.4	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 0.00737% European (non-Finnish) · 87/1,179,954 alleles

Filtering AF 0.00605% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00565%

Overall 0.00545% 88/1,613,788 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00737%	13,563
African / African-American	0.00133%	74,916

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.Tyr200Asp
Coding: c.598T>G
MANE Select: NM_015114
Type: single nucleotide variant
Location: chr12:132754717 (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-tyr200asp (accessed [today's date]).

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