Is MARK2 p.Arg664Ter (c.1990C>T) pathogenic?

MARK2 p.Arg664Ter (c.1990C>T) is classified Likely pathogenic in MARK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-07-03). Very rare (popmax 8.67e-05%, nfe); Associated with autism spectrum disorder.

What condition is associated with MARK2 p.Arg664Ter (c.1990C>T)?

MARK2 p.Arg664Ter (c.1990C>T) is associated with autism spectrum disorder (ClinVar).

How common is MARK2 p.Arg664Ter (c.1990C>T) in the general population?

MARK2 p.Arg664Ter (c.1990C>T) is very rare (popmax 8.67e-05%, nfe) (gnomAD).

MARK2 p.Arg664Ter

c.1990C>T · rs1369701108 · VCV3253638

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.67e-05%, nfe)

Conditions

autism spectrum disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (18 of 19, 16 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.30	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 4.8	GERP -0.55, phastCons 1
Overall
CADD	47.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.67e-05% European (non-Finnish) · 1/1,153,666 alleles

Overall 0.000192% 3/1,564,228 alleles · very rare exomes 1/1,411,988 · genomes 2/152,240 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00331%	30,186
European (non-Finnish)grpmax	8.67e-05%	1,153,666

Finnish 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: MARK2
Protein: p.Arg664Ter
Coding: c.1990C>T
MANE Select: NM_001039469
dbSNP: rs1369701108
Type: single nucleotide variant
Location: chr11:63908288 (GRCh38)
Gene constraint: LOEUF 0.287 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.21 · 5 PDB
Residue 664: a UniProt-annotated variant site (in mrd76; likely pathogenic); a UniProt-annotated variant site (in mrd76; pathogenic)

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

Disease context

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

Similar variants

MARK2 c.1934+1G>A Likely pathogenic ★ same condition
MARK2 c.337+1G>T Pathogenic ★ same condition
MARK2 p.Arg584Ter Pathogenic ★ same condition
MARK2 p.Gly135Arg Likely pathogenic ★ same condition
MARK2 p.Arg302Ter Uncertain significance ★ same condition
MARK2 p.Arg71Ter Conflicting classifications of pathogenicity ★ ⚠ same condition
MARK2 p.Phe194Ser Uncertain significance ★ ⚠ same condition
MARK2 c.1101+1G>A Pathogenic 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-arg664ter (accessed [today's date]).

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