ANKLE2 p.Phe523=
c.1569C>T · rs778904074 · VCV736935
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
rare (popmax 0.143%, eas)
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 -4.7 | |
| Overall | ||
| CADD | 5.776 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.143%
East Asian · 64/44,754 alleles
Filtering AF
0.115%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.105%
Overall
0.0059%
95/1,610,302 alleles · rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 0.143% | 699 |
| Admixed American | 0.0117% | 8,534 |
| Remaining individualsnot grpmax-eligible | 0.00803% | 12,452 |
| African / African-American | 0.00667% | 14,996 |
| Finnishnot grpmax-eligible | 0.00157% | 63,848 |
| European (non-Finnish) | 0.0011% | 90,562 |
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.Phe523=
- Coding
- c.1569C>T
- MANE Select
- NM_015114
- dbSNP
- rs778904074
- Type
- single nucleotide variant
- Location
- chr12:132736917 (GRCh38)
- Gene constraint
- LOEUF 0.825 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 65.14
- Residue 523
- a UniProt-annotated variant site (in mcph16; uncertain significance)
Similar variants
- 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
- ANKLE2 p.Pro377Leu 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-phe523 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown