Is MARK2 p.Val395Ala (c.1184T>C) pathogenic?

MARK2 p.Val395Ala (c.1184T>C) is classified Uncertain significance in MARK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-24). AlphaMissense: likely pathogenic (0.7573); Ultra-rare (popmax 0.022%, sas).

How common is MARK2 p.Val395Ala (c.1184T>C) in the general population?

MARK2 p.Val395Ala (c.1184T>C) is ultra-rare (popmax 0.022%, sas) (gnomAD).

What do computational predictors say about MARK2 p.Val395Ala (c.1184T>C)?

AlphaMissense predicts likely pathogenic (score 0.7573) — an in-silico prediction, not a clinical call.

MARK2 p.Val395Ala

c.1184T>C · rs761752661 · VCV2305041

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7573 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7573	likely pathogenic
REVEL	0.155	moderately benign-leaning
SaProt	LLR -7.06	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.28	donor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 6.2	GERP 0.85, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 8,317 bp · p 7.7e-13 · regional, not allelic
Overall
CADD	24.8	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 0.022% South Asian · 20/91,076 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00124% 20/1,614,072 alleles · ultra-rare exomes 20/1,461,826 · genomes 0/152,246 · joint denominator

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: MARK2
Protein: p.Val395Ala
Coding: c.1184T>C
MANE Select: NM_001039469
dbSNP: rs761752661
Type: single nucleotide variant
Location: chr11:63902280 (GRCh38)
Gene constraint: LOEUF 0.287 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.21 · 5 PDB
Residue 395: a UniProt-annotated variant site (in mrd76; likely pathogenic); a UniProt-annotated variant site (in mrd76; pathogenic); the 'disordered' region

Full MARK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MARK2 p.Val395fs Pathogenic same residue
MARK2 p.Ala432Thr Uncertain significance ★★ ⚠ same type
MARK2 p.Arg264Ser Uncertain significance ★★ ⚠ same type
MARK2 p.Arg482Ter Uncertain significance ★★ same type
MARK2 c.337+8C>G Likely benign ★★ same type
MARK2 p.Pro459= Benign ★★ same type
MARK2 p.Pro740= Benign ★★ same type
MARK2 p.Ser725= Benign ★★ 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/mark2-p-val395ala (accessed [today's date]).

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