Is ANKLE2 p.Phe418Leu (c.1252T>C) pathogenic?

ANKLE2 p.Phe418Leu (c.1252T>C) is classified Uncertain significance in ANKLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). AlphaMissense: likely pathogenic (0.9897); Very rare (popmax 0.00133%, afr).

How common is ANKLE2 p.Phe418Leu (c.1252T>C) in the general population?

ANKLE2 p.Phe418Leu (c.1252T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ANKLE2 p.Phe418Leu (c.1252T>C)?

AlphaMissense predicts likely pathogenic (score 0.9897) — an in-silico prediction, not a clinical call.

ANKLE2 p.Phe418Leu

c.1252T>C · VCV4536532

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9897 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9897	likely pathogenic · top 2% in ANKLE2
REVEL	0.443	indeterminate
SaProt	LLR -9.42	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 21 kb · p 0.32 · regional, not allelic
Overall
CADD	26.5	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 0.00133% African / African-American · 1/75,024 alleles

Overall 6.85e-05% 1/1,458,962 alleles · very rare

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.Phe418Leu
Coding: c.1252T>C
MANE Select: NM_015114
Type: single nucleotide variant
Location: chr12:132743255 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14
Residue 418: a UniProt-annotated variant site (in mcph16; uncertain significance)

Full ANKLE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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-phe418leu (accessed [today's date]).

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