Is MARK3 p.Arg570Trp (c.1708C>T) pathogenic?

MARK3 p.Arg570Trp (c.1708C>T) is classified Uncertain significance in MARK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-18). AlphaMissense: ambiguous (0.4655); Ultra-rare (popmax 0.044%, afr).

How common is MARK3 p.Arg570Trp (c.1708C>T) in the general population?

MARK3 p.Arg570Trp (c.1708C>T) is ultra-rare (popmax 0.044%, afr) (gnomAD).

What do computational predictors say about MARK3 p.Arg570Trp (c.1708C>T)?

AlphaMissense predicts ambiguous (score 0.4655) — an in-silico prediction, not a clinical call.

MARK3 p.Arg570Trp

c.1708C>T · rs376395495 · VCV2382418

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4655 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.044%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4655	ambiguous
REVEL	0.286	benign-leaning
SaProt	LLR -8.61	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 0.69, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 37 kb · p 0.031 · regional, not allelic
Overall
CADD	28.8	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 0.044% African / African-American · 33/75,044 alleles

Filtering AF 0.0321% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0281%

Overall 0.00483% 78/1,614,166 alleles · ultra-rare exomes 60/1,461,876 · genomes 18/152,290 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.044%	2,274
East Asian	0.0312%	3,205
Finnishnot grpmax-eligible	0.0203%	4,926
Middle Eastern	0.0165%	6,056
Remaining individualsnot grpmax-eligible	0.0064%	15,627
Admixed American	0.00333%	30,005
South Asian	0.0011%	91,082
European (non-Finnish)	0.000847%	118,003

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.Arg570Trp
Coding: c.1708C>T
MANE Select: NM_001128918
dbSNP: rs376395495
Type: single nucleotide variant
Location: chr14:103491898 (GRCh38)
Gene constraint: LOEUF 0.73 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.25 · 14 PDB
Residue 570: a UniProt-annotated variant site (in vipb); the 'disordered' region

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

Similar variants

MARK3 p.Arg570Gly Pathogenic 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-arg570trp (accessed [today's date]).

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