Is MARK2 p.Leu647fs (c.1939_1940del) pathogenic?

MARK2 p.Leu647fs (c.19391940del) is classified Likely pathogenic in MARK2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-11-22). Very rare (popmax 0.00332%, amr); Associated with intellectual disability.

What condition is associated with MARK2 p.Leu647fs (c.1939_1940del)?

MARK2 p.Leu647fs (c.1939_1940del) is associated with intellectual disability, autism spectrum disorder (ClinVar).

How common is MARK2 p.Leu647fs (c.1939_1940del) in the general population?

MARK2 p.Leu647fs (c.1939_1940del) is very rare (popmax 0.00332%, amr) (gnomAD).

MARK2 p.Leu647fs

c.1939_1940del · rs1252482376 · VCV3253637

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00332%, amr)

Conditions

intellectual disability

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 17 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Overall
CADD	35.0	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 0.00332% Admixed American · 1/30,114 alleles

Filtering AF 0.00108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000889%

Overall 0.00149% 20/1,344,780 alleles · very rare exomes 15/1,194,144 · genomes 5/150,636 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00332%	30,114
European (non-Finnish)	0.00172%	58,015
African / African-American	0.00152%	65,866

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.Leu647fs
Coding: c.1939_1940del
MANE Select: NM_001039469
dbSNP: rs1252482376
Type: Deletion
Location: chr11:63906091 (GRCh38)
Gene constraint: LOEUF 0.287 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.21 · 5 PDB
Residue 647: 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

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

Also linked: autism spectrum disorder

Similar variants

MARK2 p.Thr374fs Uncertain significance ★ same condition
MARK2 p.Cys723fs Pathogenic same condition
MARK2 p.Gly590fs Pathogenic same condition
MARK2 p.Phe271fs Pathogenic same condition
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

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-leu647fs (accessed [today's date]).

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