Is MARK1 p.Val466Ala (c.1397T>C) pathogenic?

MARK1 p.Val466Ala (c.1397T>C) is classified Uncertain significance in MARK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely benign (0.0739); Ultra-rare (popmax 0.0133%, nfe).

How common is MARK1 p.Val466Ala (c.1397T>C) in the general population?

MARK1 p.Val466Ala (c.1397T>C) is ultra-rare (popmax 0.0133%, nfe) (gnomAD).

What do computational predictors say about MARK1 p.Val466Ala (c.1397T>C)?

AlphaMissense predicts likely benign (score 0.0739) — an in-silico prediction, not a clinical call.

MARK1 p.Val466Ala

c.1397T>C · rs375626019 · VCV2568456

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0739 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0739	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -8.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 43 kb · p 0.00032 · regional, not allelic
Overall
CADD	18.03	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% European (non-Finnish) · 157/1,179,936 alleles

Filtering AF 0.0116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.0103% 167/1,613,694 alleles · ultra-rare exomes 162/1,461,722 · genomes 5/151,972 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0133%	7,516
Remaining individualsnot grpmax-eligible	0.0128%	7,811
African / African-American	0.00267%	37,414

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.Val466Ala
Coding: c.1397T>C
MANE Select: NM_018650
dbSNP: rs375626019
Type: single nucleotide variant
Location: chr1:220635953 (GRCh38)
Gene constraint: LOEUF 0.577 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 68.33 · 3 PDB
Residue 466: the 'disordered' region

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-val466ala (accessed [today's date]).

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