Is MARK3 p.Arg640Cys (c.1918C>T) pathogenic?

MARK3 p.Arg640Cys (c.1918C>T) is classified Uncertain significance in MARK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: ambiguous (0.3538); Very rare (popmax 0.00224%, eas).

How common is MARK3 p.Arg640Cys (c.1918C>T) in the general population?

MARK3 p.Arg640Cys (c.1918C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about MARK3 p.Arg640Cys (c.1918C>T)?

AlphaMissense predicts ambiguous (score 0.3538) — an in-silico prediction, not a clinical call.

MARK3 p.Arg640Cys

c.1918C>T · VCV4104142

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3538 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Computational evidence

Protein change
AlphaMissense	0.3538	ambiguous
REVEL	0.334	indeterminate
SaProt	LLR -8.81	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 37 kb · p 0.031 · regional, not allelic
Overall
CADD	32.0	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 0.00224% East Asian · 1/44,676 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000906%

Overall 0.00175% 28/1,603,672 alleles · very rare exomes 24/1,451,470 · genomes 4/152,202 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00645%	15,496
East Asiangrpmax	0.00224%	44,676
South Asian	0.00221%	45,281
European (non-Finnish)	0.00171%	58,619
African / African-American	0.00134%	74,524

Remaining individuals 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: MARK3
Protein: p.Arg640Cys
Coding: c.1918C>T
MANE Select: NM_001128918
Type: single nucleotide variant
Location: chr14:103502883 (GRCh38)
Gene constraint: LOEUF 0.73 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.25 · 14 PDB
Residue 640: the 'disordered' region

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-arg640cys (accessed [today's date]).

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