Is MARK2 p.Gln724Pro (c.2171A>C) pathogenic?

MARK2 p.Gln724Pro (c.2171A>C) is classified Uncertain significance in MARK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: likely benign (0.3); Ultra-rare (popmax 0.0127%, nfe).

How common is MARK2 p.Gln724Pro (c.2171A>C) in the general population?

MARK2 p.Gln724Pro (c.2171A>C) is ultra-rare (popmax 0.0127%, nfe) (gnomAD).

What do computational predictors say about MARK2 p.Gln724Pro (c.2171A>C)?

AlphaMissense predicts likely benign (score 0.3) — an in-silico prediction, not a clinical call.

MARK2 p.Gln724Pro

c.2171A>C · rs568393922 · VCV2590764

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0127%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -12.31	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.3	GERP 0.84, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 96 bp · p 0.74 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0127% European (non-Finnish) · 148/1,169,010 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0103%

Overall 0.00937% 150/1,600,644 alleles · ultra-rare exomes 143/1,448,394 · genomes 7/152,250 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0127%	7,899
Remaining individualsnot grpmax-eligible	0.00324%	30,888

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.Gln724Pro
Coding: c.2171A>C
MANE Select: NM_001039469
dbSNP: rs568393922
Type: single nucleotide variant
Location: chr11:63909041 (GRCh38)
Gene constraint: LOEUF 0.287 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.21 · 5 PDB
Residue 724: 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-gln724pro (accessed [today's date]).

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