Is ANKLE1 p.Arg467Gln (c.1400G>A) pathogenic?

ANKLE1 p.Arg467Gln (c.1400G>A) is classified Uncertain significance in ANKLE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-02). AlphaMissense: likely benign (0.1344); Ultra-rare (popmax 0.0472%, sas).

How common is ANKLE1 p.Arg467Gln (c.1400G>A) in the general population?

ANKLE1 p.Arg467Gln (c.1400G>A) is ultra-rare (popmax 0.0472%, sas) (gnomAD).

What do computational predictors say about ANKLE1 p.Arg467Gln (c.1400G>A)?

AlphaMissense predicts likely benign (score 0.1344) — an in-silico prediction, not a clinical call.

ANKLE1 p.Arg467Gln

c.1400G>A · rs141599824 · VCV2596055

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1344 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0472%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1344	likely benign
REVEL	0.306	indeterminate
SaProt	LLR -9.20	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.44, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,628 bp · p 0.11 · regional, not allelic
Overall
CADD	23.9	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 0.0472% South Asian · 43/91,084 alleles

Filtering AF 0.036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0321%

Overall 0.00725% 117/1,613,720 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0472%	2,118
Middle Eastern	0.0165%	6,050
Remaining individualsnot grpmax-eligible	0.0096%	10,413
European (non-Finnish)	0.00534%	18,728
African / African-American	0.004%	25,007
East Asian	0.00223%	44,856

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: ANKLE1
Protein: p.Arg467Gln
Coding: c.1400G>A
MANE Select: NM_152363
dbSNP: rs141599824
Type: single nucleotide variant
Location: chr19:17285454 (GRCh38)
Gene constraint: LOEUF 1.368 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.14
Residue 467: the giy-yig domain

Full ANKLE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKLE1 p.Arg467Pro Uncertain significance ★ ⚠ same residue
ANKLE1 c.461-109C>A Benign ★★ same type
ANKLE1 c.*132G>T Benign ★★ same type
ANKLE1 p.Leu524Val Benign ★★ same type
ANKLE1 p.Pro160Ser Benign ★★ same type
ANKLE1 p.Val447Met Benign ★★ same type
ANKLE1 p.Ala103Val Uncertain significance ★ ⚠ same type
ANKLE1 p.Ala143Thr 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/ankle1-p-arg467gln (accessed [today's date]).

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