Is ANKLE1 p.His45Arg (c.134A>G) pathogenic?

ANKLE1 p.His45Arg (c.134A>G) is classified Uncertain significance in ANKLE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely pathogenic (0.9332); Ultra-rare (popmax 0.0465%, eas).

How common is ANKLE1 p.His45Arg (c.134A>G) in the general population?

ANKLE1 p.His45Arg (c.134A>G) is ultra-rare (popmax 0.0465%, eas) (gnomAD).

What do computational predictors say about ANKLE1 p.His45Arg (c.134A>G)?

AlphaMissense predicts likely pathogenic (score 0.9332) — an in-silico prediction, not a clinical call.

ANKLE1 p.His45Arg

c.134A>G · rs766804036 · VCV3121389

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9332 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0465%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9332	likely pathogenic · top 3% in ANKLE1
REVEL	0.488	indeterminate
SaProt	LLR -14.30	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 1.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,628 bp · p 0.11 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0465% East Asian · 19/40,836 alleles

Filtering AF 0.0304% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0253%

Overall 0.00331% 51/1,540,364 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0465%	2,149
South Asian	0.0345%	2,895
Middle Eastern	0.0183%	5,464
Remaining individualsnot grpmax-eligible	0.00167%	59,846
European (non-Finnish)	8.73e-05%	1,145,930

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.His45Arg
Coding: c.134A>G
MANE Select: NM_152363
dbSNP: rs766804036
Type: single nucleotide variant
Location: chr19:17282128 (GRCh38)
Gene constraint: LOEUF 1.368 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.14

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

Similar variants

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
ANKLE1 p.Ala207Val 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-his45arg (accessed [today's date]).

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