Is ANKLE2 p.Arg720His (c.2159G>A) pathogenic?

ANKLE2 p.Arg720His (c.2159G>A) is classified Benign in ANKLE2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-27). AlphaMissense: likely benign (0.0753); Common (popmax 40.2%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with microcephaly 16, primary, autosomal recessive.

What condition is associated with ANKLE2 p.Arg720His (c.2159G>A)?

ANKLE2 p.Arg720His (c.2159G>A) is associated with microcephaly 16, primary, autosomal recessive (ClinVar).

What do computational predictors say about ANKLE2 p.Arg720His (c.2159G>A)?

AlphaMissense predicts likely benign (score 0.0753) — an in-silico prediction, not a clinical call.

ANKLE2 p.Arg720His

Q: How common is ANKLE2 p.Arg720His (c.2159G>A) in the general population?

ANKLE2 p.Arg720His (c.2159G>A) is common (popmax 40.2%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2159G>A · rs10781634 · VCV1192433

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0753 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 40.2%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcephaly 16, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.0753	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -6.80	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 -1.6
Regional constraint	o/e 1.04	unconstrained · MANE · 21 kb · p 0.32 · regional, not allelic
Overall
CADD	6.387	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 40.2% European (non-Finnish) · 474,720/1,179,804 alleles

Filtering AF 40.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 40.1%

Overall 37.3% 601,277/1,612,942 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	46.9%	2
Ashkenazi Jewishnot grpmax-eligible	42.7%	2
Finnishnot grpmax-eligible	41.8%	2
European (non-Finnish)grpmax	40.2%	2
South Asian	36.3%	3
Middle Eastern	36.2%	3
Remaining individualsnot grpmax-eligible	36.1%	3
Admixed American	20.8%	5
East Asian	17.3%	6
African / African-American	12%	8

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg720His
Coding: c.2159G>A
MANE Select: NM_015114
dbSNP: rs10781634
Type: single nucleotide variant
Location: chr12:132730003 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14
Residue 720: a UniProt-annotated variant site (in mcph16; uncertain significance); a UniProt-annotated variant site (in)

Full ANKLE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephaly 16, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ANKLE2 p.Arg720Cys Conflicting classifications of pathogenicity ★ same residue
ANKLE2 p.Arg624Ter Pathogenic ★★ same condition
ANKLE2 p.Val354Met Uncertain significance ★★ ⚠ same condition
ANKLE2 c.1421-138G>C Benign ★★ same condition
ANKLE2 c.1594-93A>G Benign ★★ same condition
ANKLE2 c.1700+104G>C Benign ★★ same condition
ANKLE2 c.1700+48A>G Benign ★★ same condition
ANKLE2 c.1891+84G>A Benign ★★ 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-arg720his (accessed [today's date]).

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