Is ANKLE2 p.Glu680Lys (c.2038G>A) pathogenic?

ANKLE2 p.Glu680Lys (c.2038G>A) is classified Benign in ANKLE2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-05-18). AlphaMissense: likely benign (0.0823); Common (popmax 11.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with microcephaly 16, primary, autosomal recessive.

What condition is associated with ANKLE2 p.Glu680Lys (c.2038G>A)?

ANKLE2 p.Glu680Lys (c.2038G>A) is associated with microcephaly 16, primary, autosomal recessive (ClinVar).

What do computational predictors say about ANKLE2 p.Glu680Lys (c.2038G>A)?

AlphaMissense predicts likely benign (score 0.0823) — an in-silico prediction, not a clinical call.

ANKLE2 p.Glu680Lys

Q: How common is ANKLE2 p.Glu680Lys (c.2038G>A) in the general population?

ANKLE2 p.Glu680Lys (c.2038G>A) is common (popmax 11.1%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2038G>A · rs78905764 · VCV1098725

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0823 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 11.1%, eas) — 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	0.0823	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -7.13	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 3.5	phastCons 0.28
Regional constraint	o/e 1.04	unconstrained · MANE · 21 kb · p 0.32 · regional, not allelic
Overall
CADD	16.3	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 11.1% East Asian · 4,959/44,852 alleles

Filtering AF 10.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.7%

Overall 6.99% 112,726/1,612,270 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	11.1%	9
Amishnot grpmax-eligible	10.5%	10
Ashkenazi Jewishnot grpmax-eligible	9.61%	10
Finnishnot grpmax-eligible	8.93%	11
European (non-Finnish)	7.32%	14
Remaining individualsnot grpmax-eligible	7.15%	14
Middle Eastern	6.52%	15
South Asian	5.33%	19
Admixed American	3.82%	26
African / African-American	1.12%	89

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.Glu680Lys
Coding: c.2038G>A
MANE Select: NM_015114
dbSNP: rs78905764
Type: single nucleotide variant
Location: chr12:132730124 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14
Residue 680: 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

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

Similar variants

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
ANKLE2 c.641-35T>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-glu680lys (accessed [today's date]).

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