Is MARK2 p.Glu666Ter (c.1996G>T) pathogenic?

MARK2 p.Glu666Ter (c.1996G>T) is classified Likely pathogenic in MARK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-24). No allele count reported in gnomAD v4.1 (AN 1,563,606).

How common is MARK2 p.Glu666Ter (c.1996G>T) in the general population?

MARK2 p.Glu666Ter (c.1996G>T) is no allele count reported in gnomAD v4.1 (AN 1,563,606) (gnomAD).

MARK2 p.Glu666Ter

c.1996G>T · VCV4885952

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,563,606)

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, 10 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	Δ0.39	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Overall
CADD	51.0	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

No allele count reported in gnomAD v4.1 (AN 1,563,606). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MARK2
Protein: p.Glu666Ter
Coding: c.1996G>T
MANE Select: NM_001039469
Type: single nucleotide variant
Location: chr11:63908294 (GRCh38)
Gene constraint: LOEUF 0.287 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.21 · 5 PDB
Residue 666: 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

Similar variants

MARK2 p.Ala432Thr Uncertain significance ★★ ⚠ same type
MARK2 p.Arg264Ser Uncertain significance ★★ ⚠ same type
MARK2 p.Arg482Ter Uncertain significance ★★ same type
MARK2 c.337+8C>G Likely benign ★★ same type
MARK2 p.Pro459= Benign ★★ same type
MARK2 p.Pro740= Benign ★★ same type
MARK2 p.Ser725= Benign ★★ same type
MARK2 c.1102-1G>C Likely pathogenic ★ same type

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-glu666ter (accessed [today's date]).

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