Is ANKLE2 p.Ala483Val (c.1448C>T) pathogenic?

ANKLE2 p.Ala483Val (c.1448C>T) is classified Uncertain significance in ANKLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-10). AlphaMissense: ambiguous (0.3616); Very rare (popmax 0.0044%, sas); Associated with Inborn genetic diseases.

What condition is associated with ANKLE2 p.Ala483Val (c.1448C>T)?

ANKLE2 p.Ala483Val (c.1448C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ANKLE2 p.Ala483Val (c.1448C>T) in the general population?

ANKLE2 p.Ala483Val (c.1448C>T) is very rare (popmax 0.0044%, sas) (gnomAD).

What do computational predictors say about ANKLE2 p.Ala483Val (c.1448C>T)?

AlphaMissense predicts ambiguous (score 0.3616) — an in-silico prediction, not a clinical call.

ANKLE2 p.Ala483Val

c.1448C>T · rs770590525 · VCV2230070

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3616 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0044%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3616	ambiguous
REVEL	0.479	indeterminate
SaProt	LLR -8.50	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 21 kb · p 0.32 · regional, not allelic
Overall
CADD	29.8	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 0.0044% South Asian · 4/90,826 alleles

Filtering AF 0.00327% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00355% 57/1,607,668 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0044%	22,706
European (non-Finnish)	0.00425%	23,509
Remaining individualsnot grpmax-eligible	0.00322%	31,040
African / African-American	0.00134%	74,838

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.Ala483Val
Coding: c.1448C>T
MANE Select: NM_015114
dbSNP: rs770590525
Type: single nucleotide variant
Location: chr12:132737038 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14
Residue 483: 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-ala483val (accessed [today's date]).

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