Is ANKLE2 p.Pro333Ser (c.997C>T) pathogenic?

ANKLE2 p.Pro333Ser (c.997C>T) is classified Uncertain significance in ANKLE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-06). AlphaMissense: likely pathogenic (0.9951); Absent from gnomAD v4.1; Associated with microcephaly 16, primary, autosomal recessive.

What condition is associated with ANKLE2 p.Pro333Ser (c.997C>T)?

ANKLE2 p.Pro333Ser (c.997C>T) is associated with microcephaly 16, primary, autosomal recessive (ClinVar).

How common is ANKLE2 p.Pro333Ser (c.997C>T) in the general population?

ANKLE2 p.Pro333Ser (c.997C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ANKLE2 p.Pro333Ser (c.997C>T)?

AlphaMissense predicts likely pathogenic (score 0.9951) — an in-silico prediction, not a clinical call.

ANKLE2 p.Pro333Ser

c.997C>T · rs2542394621 · VCV3235060

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9951 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcephaly 16, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.9951	likely pathogenic · top 1% in ANKLE2
REVEL	0.761	pathogenic-leaning
SaProt	LLR -11.17	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 78 bp · p 0.00096 · regional, not allelic
Overall
CADD	26.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ANKLE2
Protein: p.Pro333Ser
Coding: c.997C>T
MANE Select: NM_015114
dbSNP: rs2542394621
Type: single nucleotide variant
Location: chr12:132748182 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.14
Residue 333: 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-pro333ser (accessed [today's date]).

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