Is MARCKS p.Ala217Val (c.650C>T) pathogenic?

MARCKS p.Ala217Val (c.650C>T) is classified Uncertain significance in MARCKS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely benign (0.0878); Very rare (popmax 0.000226%, nfe).

How common is MARCKS p.Ala217Val (c.650C>T) in the general population?

MARCKS p.Ala217Val (c.650C>T) is very rare (popmax 0.000226%, nfe) (gnomAD).

What do computational predictors say about MARCKS p.Ala217Val (c.650C>T)?

AlphaMissense predicts likely benign (score 0.0878) — an in-silico prediction, not a clinical call.

MARCKS p.Ala217Val

c.650C>T · VCV4104039

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0878 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000226%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0878	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -9.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.094, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 2,830 bp · p 9e-12 · regional, not allelic
Overall
CADD	21.2	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 0.000226% European (non-Finnish) · 2/883,928 alleles

Filtering AF 3.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000215% 2/928,702 alleles · very rare

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: MARCKS
Protein: p.Ala217Val
Coding: c.650C>T
MANE Select: NM_002356
Type: single nucleotide variant
Location: chr6:113860230 (GRCh38)
Gene constraint: LOEUF 1.86 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.42 · 1 PDB
Residue 217: the 'disordered' region

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

Similar variants

MARCKS p.Ala100Asp Uncertain significance ★ ⚠ same type
MARCKS p.Ala142Asp Uncertain significance ★ ⚠ same type
MARCKS p.Ala184Val Uncertain significance ★ ⚠ same type
MARCKS p.Ala201Asp Uncertain significance ★ ⚠ same type
MARCKS p.Ala201Val Uncertain significance ★ ⚠ same type
MARCKS p.Ala203Val Uncertain significance ★ ⚠ same type
MARCKS p.Ala209Val Uncertain significance ★ ⚠ same type
MARCKS p.Ala222Glu 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/marcks-p-ala217val (accessed [today's date]).

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