Is MARK1 p.Ile66Val (c.196A>G) pathogenic?

MARK1 p.Ile66Val (c.196A>G) is classified Uncertain significance in MARK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: ambiguous (0.4547); Ultra-rare (popmax 0.0493%, mid).

How common is MARK1 p.Ile66Val (c.196A>G) in the general population?

MARK1 p.Ile66Val (c.196A>G) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about MARK1 p.Ile66Val (c.196A>G)?

AlphaMissense predicts ambiguous (score 0.4547) — an in-silico prediction, not a clinical call.

MARK1 p.Ile66Val

c.196A>G · VCV4104120

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4547 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Computational evidence

Protein change
AlphaMissense	0.4547	ambiguous
REVEL	0.303	indeterminate
SaProt	LLR -8.32	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.2	GERP 2.2, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 70 kb · p 0.014 · regional, not allelic
Overall
CADD	26.0	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 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0179%

Overall 0.0175% 282/1,613,986 alleles · ultra-rare exomes 266/1,461,802 · genomes 16/152,184 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
Remaining individualsnot grpmax-eligible	0.0256%	3,905
European (non-Finnish)	0.0208%	4,797
Admixed American	0.0117%	8,571
South Asian	0.00878%	11,386
African / African-American	0.00267%	37,469

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: MARK1
Protein: p.Ile66Val
Coding: c.196A>G
MANE Select: NM_018650
Type: single nucleotide variant
Location: chr1:220579498 (GRCh38)
Gene constraint: LOEUF 0.577 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 68.33 · 3 PDB
Residue 66: the protein kinase domain; a binding site; a β-strand

Full MARK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MARK1 p.Arg577Gln Uncertain significance ★★ ⚠ same type
MARK1 p.Ala541Pro Benign ★★ same type
MARK1 p.Ala352Thr Uncertain significance ★ ⚠ same type
MARK1 p.Ala442Asp Uncertain significance ★ ⚠ same type
MARK1 p.Arg268Gln Uncertain significance ★ ⚠ same type
MARK1 p.Arg391Gln Uncertain significance ★ ⚠ same type
MARK1 p.Arg421Cys Uncertain significance ★ ⚠ same type
MARK1 p.Arg42Trp 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/mark1-p-ile66val (accessed [today's date]).

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