Is ANKLE2 p.Arg654Gln (c.1961G>A) pathogenic?

ANKLE2 p.Arg654Gln (c.1961G>A) is classified Benign/Likely benign in ANKLE2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-08-08). AlphaMissense: likely benign (0.0868); Rare (popmax 0.961%, afr); Associated with Inborn genetic diseases.

What condition is associated with ANKLE2 p.Arg654Gln (c.1961G>A)?

ANKLE2 p.Arg654Gln (c.1961G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ANKLE2 p.Arg654Gln (c.1961G>A) in the general population?

ANKLE2 p.Arg654Gln (c.1961G>A) is rare (popmax 0.961%, afr) (gnomAD).

What do computational predictors say about ANKLE2 p.Arg654Gln (c.1961G>A)?

AlphaMissense predicts likely benign (score 0.0868) — an in-silico prediction, not a clinical call.

ANKLE2 p.Arg654Gln

c.1961G>A · rs77116800 · VCV730329

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0868 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.961%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0868	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -6.60	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 -1.2
Regional constraint	o/e 1.04	unconstrained · MANE · 21 kb · p 0.32 · regional, not allelic
Overall
CADD	15.48	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 0.961% African / African-American · 713/74,204 alleles

Filtering AF 0.902% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.879%

Overall 0.0554% 886/1,598,212 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.961%	104
Ashkenazi Jewishnot grpmax-eligible	0.107%	934
Remaining individualsnot grpmax-eligible	0.081%	1,234
Middle Eastern	0.0502%	1,991
Admixed American	0.0442%	2,262
European (non-Finnish)	0.00529%	18,909
South Asian	0.00221%	45,194

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.Arg654Gln
Coding: c.1961G>A
MANE Select: NM_015114
dbSNP: rs77116800
Type: single nucleotide variant
Location: chr12:132730201 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14
Residue 654: 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-arg654gln (accessed [today's date]).

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