Is MARK2 p.Gly22Val (c.65G>T) pathogenic?

MARK2 p.Gly22Val (c.65G>T) is classified Uncertain significance in MARK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely benign (0.0952); Very rare (popmax 0.00136%, nfe).

How common is MARK2 p.Gly22Val (c.65G>T) in the general population?

MARK2 p.Gly22Val (c.65G>T) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about MARK2 p.Gly22Val (c.65G>T)?

AlphaMissense predicts likely benign (score 0.0952) — an in-silico prediction, not a clinical call.

MARK2 p.Gly22Val

c.65G>T · VCV4104131

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0952 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0952	likely benign
REVEL	0.304	indeterminate
SaProt	LLR -7.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.6	GERP 0.75, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 56 kb · p 0.12 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00136% European (non-Finnish) · 16/1,179,120 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.000992% 16/1,612,686 alleles · very rare exomes 15/1,460,570 · genomes 1/152,116 · joint denominator

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.Gly22Val
Coding: c.65G>T
MANE Select: NM_001039469
Type: single nucleotide variant
Location: chr11:63895169 (GRCh38)
Gene constraint: LOEUF 0.287 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.21 · 5 PDB
Residue 22: the 'disordered' region

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-gly22val (accessed [today's date]).

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