Is MARK3 p.Val336Met (c.1006G>A) pathogenic?

MARK3 p.Val336Met (c.1006G>A) is classified Uncertain significance in MARK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-06). AlphaMissense: likely benign (0.143); Ultra-rare (popmax 0.0137%, amr).

How common is MARK3 p.Val336Met (c.1006G>A) in the general population?

MARK3 p.Val336Met (c.1006G>A) is ultra-rare (popmax 0.0137%, amr) (gnomAD).

What do computational predictors say about MARK3 p.Val336Met (c.1006G>A)?

AlphaMissense predicts likely benign (score 0.143) — an in-silico prediction, not a clinical call.

MARK3 p.Val336Met

c.1006G>A · VCV3870626

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.143 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0137%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.143	likely benign
REVEL	0.234	benign-leaning
SaProt	LLR -7.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 37 kb · p 0.031 · regional, not allelic
Overall
CADD	21.9	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 0.0137% Admixed American · 8/58,578 alleles

Filtering AF 0.00675% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00492%

Overall 0.00054% 8/1,482,634 alleles · ultra-rare exomes 7/1,330,830 · genomes 1/151,804 · joint denominator

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.Val336Met
Coding: c.1006G>A
MANE Select: NM_001128918
Type: single nucleotide variant
Location: chr14:103467087 (GRCh38)
Gene constraint: LOEUF 0.73 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.25 · 14 PDB
Residue 336: the uba domain; an α-helix

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

Similar variants

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
MARK3 p.Arg305Lys 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-val336met (accessed [today's date]).

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