Is ANKLE2 p.Phe549Val (c.1645T>G) pathogenic?

ANKLE2 p.Phe549Val (c.1645T>G) is classified Uncertain significance in ANKLE2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-26). AlphaMissense: likely benign (0.2062); Ultra-rare (popmax 0.0484%, amr); Associated with Inborn genetic diseases.

What condition is associated with ANKLE2 p.Phe549Val (c.1645T>G)?

ANKLE2 p.Phe549Val (c.1645T>G) is associated with Inborn genetic diseases (ClinVar).

How common is ANKLE2 p.Phe549Val (c.1645T>G) in the general population?

ANKLE2 p.Phe549Val (c.1645T>G) is ultra-rare (popmax 0.0484%, amr) (gnomAD).

What do computational predictors say about ANKLE2 p.Phe549Val (c.1645T>G)?

AlphaMissense predicts likely benign (score 0.2062) — an in-silico prediction, not a clinical call.

ANKLE2 p.Phe549Val

c.1645T>G · rs202029547 · VCV2505012

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2062 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0484%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2062	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -5.06	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 3	phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 21 kb · p 0.32 · regional, not allelic
Overall
CADD	18.08	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 0.0484% Admixed American · 29/59,956 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.00341% 55/1,613,990 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0484%	2,067
Remaining individualsnot grpmax-eligible	0.008%	12,501
South Asian	0.0022%	45,531
European (non-Finnish)	0.00153%	65,555
African / African-American	0.00133%	75,048

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.Phe549Val
Coding: c.1645T>G
MANE Select: NM_015114
dbSNP: rs202029547
Type: single nucleotide variant
Location: chr12:132735461 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14
Residue 549: 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.Pro377Leu Uncertain significance ★★ ⚠ same condition
ANKLE2 p.Pro37Arg Uncertain significance ★★ ⚠ same condition
ANKLE2 p.Pro516Leu 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-phe549val (accessed [today's date]).

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