Is ANKLE2 p.Arg536Cys (c.1606C>T) pathogenic?

ANKLE2 p.Arg536Cys (c.1606C>T) is classified Uncertain significance in ANKLE2 (ClinVar, Single submitter, 2 submitters; last evaluated 2019-11-26). AlphaMissense: likely benign (0.1823); Very rare (popmax 0.00223%, eas); Associated with microcephaly 16, primary, autosomal recessive.

What condition is associated with ANKLE2 p.Arg536Cys (c.1606C>T)?

ANKLE2 p.Arg536Cys (c.1606C>T) is associated with microcephaly 16, primary, autosomal recessive (ClinVar).

How common is ANKLE2 p.Arg536Cys (c.1606C>T) in the general population?

ANKLE2 p.Arg536Cys (c.1606C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ANKLE2 p.Arg536Cys (c.1606C>T)?

AlphaMissense predicts likely benign (score 0.1823) — an in-silico prediction, not a clinical call.

ANKLE2 p.Arg536Cys

c.1606C>T · rs761627940 · VCV978453

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1823 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcephaly 16, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.1823	likely benign
REVEL	0.242	benign-leaning
SaProt	LLR -14.18	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 21 kb · p 0.32 · regional, not allelic
Overall
CADD	26.4	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 0.00223% East Asian · 1/44,872 alleles

Filtering AF 0.000366% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000274% 4/1,460,036 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,872
South Asian	0.0022%	45,403
Admixed American	0.00168%	59,468

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.Arg536Cys
Coding: c.1606C>T
MANE Select: NM_015114
dbSNP: rs761627940
Type: single nucleotide variant
Location: chr12:132735500 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14
Residue 536: 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-arg536cys (accessed [today's date]).

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