Is MARK2 p.Ala216fs (c.645_646insA) pathogenic?

MARK2 p.Ala216fs (c.645646insA) is classified Uncertain significance in MARK2 (ClinVar, Single submitter, 2 submitters). Associated with autism.

What condition is associated with MARK2 p.Ala216fs (c.645_646insA)?

MARK2 p.Ala216fs (c.645_646insA) is associated with autism, intellectual developmental disorder, autosomal dominant 76 (ClinVar).

MARK2 p.Ala216fs

c.645_646insA · VCV3900984

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

autism

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 8 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -8.4	GERP -3.8

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: MARK2
Protein: p.Ala216fs
Coding: c.645_646insA
MANE Select: NM_001039469
Type: Insertion
Location: chr11:63899987 (GRCh38)
Gene constraint: LOEUF 0.287 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.21 · 5 PDB
Residue 216: the protein kinase domain; a UniProt-annotated variant site (in mrd76; likely pathogenic)

Full MARK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual developmental disorder, autosomal dominant 76

Similar variants

MARK2 p.Ala432Thr Uncertain significance ★★ ⚠ same condition
MARK2 c.2006+2T>G Likely pathogenic ★ same condition
MARK2 c.337+1G>T Pathogenic ★ same condition
MARK2 p.Gly135Arg Likely pathogenic ★ same condition
MARK2 p.Gly580fs Pathogenic ★ same condition
MARK2 p.Tyr215Ter Likely pathogenic ★ same condition
MARK2 p.Tyr267Ter Pathogenic ★ same condition
MARK2 c.1101+5G>A Uncertain significance ★ 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/mark2-p-ala216fs (accessed [today's date]).

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