Is MARK3 p.Ile679Met (c.2037C>G) pathogenic?

MARK3 p.Ile679Met (c.2037C>G) is classified Uncertain significance in MARK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-25). AlphaMissense: likely pathogenic (0.7073); Very rare (popmax 0.00636%, nfe).

How common is MARK3 p.Ile679Met (c.2037C>G) in the general population?

MARK3 p.Ile679Met (c.2037C>G) is very rare (popmax 0.00636%, nfe) (gnomAD).

What do computational predictors say about MARK3 p.Ile679Met (c.2037C>G)?

AlphaMissense predicts likely pathogenic (score 0.7073) — an in-silico prediction, not a clinical call.

MARK3 p.Ile679Met

c.2037C>G · rs371959467 · VCV2248802

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7073 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00636%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7073	likely pathogenic
REVEL	0.348	indeterminate
SaProt	LLR -13.27	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.68, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 37 kb · p 0.031 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00636% European (non-Finnish) · 75/1,180,062 alleles

Filtering AF 0.00519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00473%

Overall 0.00489% 79/1,614,146 alleles · very rare exomes 67/1,461,892 · genomes 12/152,254 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00636%	15,734
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.00133%	74,950

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: MARK3
Protein: p.Ile679Met
Coding: c.2037C>G
MANE Select: NM_001128918
dbSNP: rs371959467
Type: single nucleotide variant
Location: chr14:103503002 (GRCh38)
Gene constraint: LOEUF 0.73 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.25 · 14 PDB

Full MARK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MARK3 p.Ile679Val Uncertain significance ★ ⚠ same residue
MARK3 c.413-4A>G Benign ★★ same type
MARK3 c.1917-11A>G Uncertain significance ★ same type
MARK3 p.Ala373Ser Uncertain significance ★ ⚠ same type
MARK3 p.Ala481Gly Uncertain significance ★ ⚠ same type
MARK3 p.Ala739Val Uncertain significance ★ ⚠ same type
MARK3 p.Ala748Asp Uncertain significance ★ ⚠ same type
MARK3 p.Arg262Lys Uncertain significance ★ ⚠ 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/mark3-p-ile679met (accessed [today's date]).

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