Is MARK4 p.Arg578Trp (c.1732C>T) pathogenic?

MARK4 p.Arg578Trp (c.1732C>T) is classified Uncertain significance in MARK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-09). AlphaMissense: ambiguous (0.3412); Ultra-rare (popmax 0.0217%, mid).

How common is MARK4 p.Arg578Trp (c.1732C>T) in the general population?

MARK4 p.Arg578Trp (c.1732C>T) is ultra-rare (popmax 0.0217%, mid) (gnomAD).

What do computational predictors say about MARK4 p.Arg578Trp (c.1732C>T)?

AlphaMissense predicts ambiguous (score 0.3412) — an in-silico prediction, not a clinical call.

MARK4 p.Arg578Trp

c.1732C>T · VCV3293343

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3412 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3412	ambiguous
REVEL	0.29	benign-leaning
SaProt	LLR -7.04	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 0.63	GERP -0.67, phastCons 0.95
Regional constraint	o/e 0.88	unconstrained · MANE · 24 kb · p 0.0023 · regional, not allelic
Overall
CADD	24.9	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 0.0217% Middle Eastern · 1/4,600 alleles

Filtering AF 0.00191% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00221% 26/1,177,298 alleles · ultra-rare exomes 25/1,035,156 · genomes 1/142,142 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0217%	4,600
European (non-Finnish)	0.00283%	35,380
South Asian	0.0013%	76,752

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: MARK4
Protein: p.Arg578Trp
Coding: c.1732C>T
MANE Select: NM_001199867
Type: single nucleotide variant
Location: chr19:45297809 (GRCh38)
Gene constraint: LOEUF 0.361 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.97 · 2 PDB
Residue 578: the 'disordered' region

Full MARK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MARK4 p.Leu226= Benign ★★ same type
MARK4 p.Thr461= Benign ★★ same type
MARK4 p.Ala168Ser Uncertain significance ★ ⚠ same type
MARK4 p.Ala389Val Uncertain significance ★ ⚠ same type
MARK4 p.Ala457Val Uncertain significance ★ ⚠ same type
MARK4 p.Ala462Val Uncertain significance ★ ⚠ same type
MARK4 p.Ala479Thr Uncertain significance ★ ⚠ same type
MARK4 p.Ala47Thr 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/mark4-p-arg578trp (accessed [today's date]).

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