Is MARK2 p.Ser725= (c.2175C>T) pathogenic?

MARK2 p.Ser725= (c.2175C>T) is classified Benign in MARK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-07-23). Common (popmax 5.24%, afr) — too common for a highly-penetrant pathogenic allele.

MARK2 p.Ser725=

Q: How common is MARK2 p.Ser725= (c.2175C>T) in the general population?

MARK2 p.Ser725= (c.2175C>T) is common (popmax 5.24%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2175C>T · rs320106 · VCV789488

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 5.24%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.1	GERP -1.7
Overall
CADD	7.435	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.24% African / African-American · 3,920/74,810 alleles

Filtering AF 5.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.05%

Overall 0.304% 4,866/1,601,332 alleles · common exomes 2,483/1,449,018 · genomes 2,383/152,314 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.24%	19
Admixed American	0.513%	195
Remaining individualsnot grpmax-eligible	0.45%	222
Middle Eastern	0.432%	232
Ashkenazi Jewishnot grpmax-eligible	0.309%	324
European (non-Finnish)	0.0205%	4,873
South Asian	0.0044%	22,705

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.Ser725=
Coding: c.2175C>T
MANE Select: NM_001039469
dbSNP: rs320106
Type: single nucleotide variant
Location: chr11:63909045 (GRCh38)
Gene constraint: LOEUF 0.287 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.21 · 5 PDB
Residue 725: 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 c.1102-1G>C Likely pathogenic ★ same type
MARK2 c.1934+1G>A 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-ser725 (accessed [today's date]).

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