Is MARK2 p.Phe649Cys (c.1946T>G) pathogenic?

MARK2 p.Phe649Cys (c.1946T>G) is classified Uncertain significance in MARK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-25). AlphaMissense: ambiguous (0.4994); Very rare (popmax 0.00105%, nfe).

How common is MARK2 p.Phe649Cys (c.1946T>G) in the general population?

MARK2 p.Phe649Cys (c.1946T>G) is very rare (popmax 0.00105%, nfe) (gnomAD).

What do computational predictors say about MARK2 p.Phe649Cys (c.1946T>G)?

AlphaMissense predicts ambiguous (score 0.4994) — an in-silico prediction, not a clinical call.

MARK2 p.Phe649Cys

c.1946T>G · VCV3870617

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4994 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00105%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4994	ambiguous
REVEL	0.348	indeterminate
SaProt	LLR -10.64	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 8,317 bp · p 7.7e-13 · regional, not allelic
Overall
CADD	34.0	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 0.00105% European (non-Finnish) · 11/1,048,560 alleles

Filtering AF 0.000563% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000411%

Overall 0.000887% 12/1,353,482 alleles · very rare exomes 11/1,201,956 · genomes 1/151,526 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00205%	48,898
European (non-Finnish)grpmax	0.00105%	95,323

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.Phe649Cys
Coding: c.1946T>G
MANE Select: NM_001039469
Type: single nucleotide variant
Location: chr11:63906099 (GRCh38)
Gene constraint: LOEUF 0.287 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.21 · 5 PDB
Residue 649: 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-phe649cys (accessed [today's date]).

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