Is MARK4 p.Arg517Cys (c.1549C>T) pathogenic?

MARK4 p.Arg517Cys (c.1549C>T) is classified Uncertain significance in MARK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-14). AlphaMissense: ambiguous (0.4275); Ultra-rare (popmax 0.0227%, afr).

How common is MARK4 p.Arg517Cys (c.1549C>T) in the general population?

MARK4 p.Arg517Cys (c.1549C>T) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about MARK4 p.Arg517Cys (c.1549C>T)?

AlphaMissense predicts ambiguous (score 0.4275) — an in-silico prediction, not a clinical call.

MARK4 p.Arg517Cys

c.1549C>T · rs372480258 · VCV2612182

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4275 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4275	ambiguous
REVEL	0.29	benign-leaning
SaProt	LLR -10.72	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -0.55, phastCons 0.99
Regional constraint	o/e 0.88	unconstrained · MANE · 24 kb · p 0.0023 · regional, not allelic
Overall
CADD	33.0	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 0.0227% African / African-American · 17/74,890 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.00198% 32/1,614,000 alleles · ultra-rare exomes 20/1,461,876 · genomes 12/152,124 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,405
South Asian	0.00329%	30,363
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)	0.000847%	118,004

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.Arg517Cys
Coding: c.1549C>T
MANE Select: NM_001199867
dbSNP: rs372480258
Type: single nucleotide variant
Location: chr19:45294403 (GRCh38)
Gene constraint: LOEUF 0.361 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.97 · 2 PDB
Residue 517: the 'disordered' region

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

Similar variants

MARK4 p.Arg517His Uncertain significance ★ ⚠ same residue
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

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-arg517cys (accessed [today's date]).

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