Is MARK1 p.Val515Ile (c.1543G>A) pathogenic?

MARK1 p.Val515Ile (c.1543G>A) is classified Uncertain significance in MARK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely benign (0.0701); Very rare (popmax 0.00667%, amr).

How common is MARK1 p.Val515Ile (c.1543G>A) in the general population?

MARK1 p.Val515Ile (c.1543G>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about MARK1 p.Val515Ile (c.1543G>A)?

AlphaMissense predicts likely benign (score 0.0701) — an in-silico prediction, not a clinical call.

MARK1 p.Val515Ile

c.1543G>A · rs780288227 · VCV3123655

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0701 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0701	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -7.09	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 -0.51	GERP -3.2
Regional constraint	o/e 0.85	unconstrained · MANE · 43 kb · p 0.00032 · regional, not allelic
Overall
CADD	0.079	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 0.00667% Admixed American · 4/59,968 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00062% 10/1,613,338 alleles · very rare exomes 8/1,461,216 · genomes 2/152,122 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,992
South Asian	0.0033%	30,342
East Asian	0.00223%	44,870
European (non-Finnish)	0.00017%	589,772

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.Val515Ile
Coding: c.1543G>A
MANE Select: NM_018650
dbSNP: rs780288227
Type: single nucleotide variant
Location: chr1:220650692 (GRCh38)
Gene constraint: LOEUF 0.577 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 68.33 · 3 PDB

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-val515ile (accessed [today's date]).

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