Is ANKLE2 p.Ser288Leu (c.863C>T) pathogenic?

ANKLE2 p.Ser288Leu (c.863C>T) is classified Likely benign in ANKLE2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-07-01). AlphaMissense: likely benign (0.075); Rare (popmax 0.493%, afr).

How common is ANKLE2 p.Ser288Leu (c.863C>T) in the general population?

ANKLE2 p.Ser288Leu (c.863C>T) is rare (popmax 0.493%, afr) (gnomAD).

What do computational predictors say about ANKLE2 p.Ser288Leu (c.863C>T)?

AlphaMissense predicts likely benign (score 0.075) — an in-silico prediction, not a clinical call.

ANKLE2 p.Ser288Leu

c.863C>T · rs185584106 · VCV730330

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.075 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.493%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.075	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.99 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.6	phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 14 kb · p 0.17 · regional, not allelic
Overall
CADD	22.4	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 0.493% African / African-American · 370/75,034 alleles

Filtering AF 0.452% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.435%

Overall 0.0279% 450/1,613,906 alleles · rare exomes 257/1,461,656 · genomes 193/152,250 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.493%	203
Remaining individualsnot grpmax-eligible	0.0416%	2,404
Admixed American	0.0333%	3,001
South Asian	0.0275%	3,634
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
European (non-Finnish)	0.000678%	147,503

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.Ser288Leu
Coding: c.863C>T
MANE Select: NM_015114
dbSNP: rs185584106
Type: single nucleotide variant
Location: chr12:132748316 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14
Residue 288: 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-ser288leu (accessed [today's date]).

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