Is ANKLE2 p.Ala930Val (c.2789C>T) pathogenic?

ANKLE2 p.Ala930Val (c.2789C>T) is classified Uncertain significance in ANKLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: likely benign (0.1104); Ultra-rare (popmax 0.0142%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ANKLE2 p.Ala930Val (c.2789C>T)?

ANKLE2 p.Ala930Val (c.2789C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ANKLE2 p.Ala930Val (c.2789C>T) in the general population?

ANKLE2 p.Ala930Val (c.2789C>T) is ultra-rare (popmax 0.0142%, nfe) (gnomAD).

What do computational predictors say about ANKLE2 p.Ala930Val (c.2789C>T)?

AlphaMissense predicts likely benign (score 0.1104) — an in-silico prediction, not a clinical call.

ANKLE2 p.Ala930Val

c.2789C>T · VCV4099483

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1104 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0142%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1104	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -7.46	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 1.3	phastCons 0.001
Regional constraint	o/e 1.04	unconstrained · MANE · 21 kb · p 0.32 · regional, not allelic
Overall
CADD	10.8	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 0.0142% European (non-Finnish) · 164/1,153,542 alleles

Filtering AF 0.0124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.0109% 171/1,562,684 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0142%	7,034
Remaining individualsnot grpmax-eligible	0.00496%	20,153
African / African-American	0.00272%	36,800
South Asian	0.00235%	42,489

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.Ala930Val
Coding: c.2789C>T
MANE Select: NM_015114
Type: single nucleotide variant
Location: chr12:132727270 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14
Residue 930: a UniProt-annotated variant site (in mcph16; uncertain significance); a UniProt-annotated variant site (in mcph16)

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-ala930val (accessed [today's date]).

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