Is MARK2 p.Pro556Leu (c.1667C>T) pathogenic?

MARK2 p.Pro556Leu (c.1667C>T) is classified Uncertain significance in MARK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-02). AlphaMissense: likely benign (0.0762); Very rare (popmax 0.00459%, eas); Associated with intellectual developmental disorder, autosomal dominant 76.

What condition is associated with MARK2 p.Pro556Leu (c.1667C>T)?

MARK2 p.Pro556Leu (c.1667C>T) is associated with intellectual developmental disorder, autosomal dominant 76 (ClinVar).

How common is MARK2 p.Pro556Leu (c.1667C>T) in the general population?

MARK2 p.Pro556Leu (c.1667C>T) is very rare (popmax 0.00459%, eas) (gnomAD).

What do computational predictors say about MARK2 p.Pro556Leu (c.1667C>T)?

AlphaMissense predicts likely benign (score 0.0762) — an in-silico prediction, not a clinical call.

MARK2 p.Pro556Leu

c.1667C>T · VCV4882601

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0762 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00459%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder, autosomal dominant 76

Computational evidence

Protein change
AlphaMissense	0.0762	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -7.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.71 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.8	GERP 0.58, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 8,317 bp · p 7.7e-13 · regional, not allelic
Overall
CADD	26.0	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 0.00459% East Asian · 2/43,530 alleles

Filtering AF 0.000762% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000316%

Overall 0.00196% 31/1,579,636 alleles · very rare exomes 28/1,427,560 · genomes 3/152,076 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0345%	2,900
East Asiangrpmax	0.00459%	21,765
South Asian	0.00113%	88,356
European (non-Finnish)	0.000856%	116,844

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.Pro556Leu
Coding: c.1667C>T
MANE Select: NM_001039469
Type: single nucleotide variant
Location: chr11:63904138 (GRCh38)
Gene constraint: LOEUF 0.287 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.21 · 5 PDB
Residue 556: a UniProt-annotated variant site (in mrd76; likely pathogenic); a UniProt-annotated variant site (in mrd76; pathogenic); the 'disordered' region

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

Disease context

intellectual developmental disorder, autosomal dominant 76 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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 c.1101+5G>A Uncertain significance ★ same condition
MARK2 p.Arg302Ter Uncertain significance ★ same condition
MARK2 p.Arg71Ter Conflicting classifications of pathogenicity ★ ⚠ same condition
MARK2 p.Asp410Glu 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-pro556leu (accessed [today's date]).

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