Is MARCKS p.Ser134Phe (c.401C>T) pathogenic?

MARCKS p.Ser134Phe (c.401C>T) is classified Uncertain significance in MARCKS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: ambiguous (0.5325); Very rare (popmax 8.67e-05%, nfe).

How common is MARCKS p.Ser134Phe (c.401C>T) in the general population?

MARCKS p.Ser134Phe (c.401C>T) is very rare (popmax 8.67e-05%, nfe) (gnomAD).

What do computational predictors say about MARCKS p.Ser134Phe (c.401C>T)?

AlphaMissense predicts ambiguous (score 0.5325) — an in-silico prediction, not a clinical call.

MARCKS p.Ser134Phe

c.401C>T · VCV4549891

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5325 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.67e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5325	ambiguous
REVEL	0.042	moderately benign-leaning
SaProt	LLR -11.17	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP 1.4, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 2,830 bp · p 9e-12 · regional, not allelic
Overall
CADD	25.3	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 8.67e-05% European (non-Finnish) · 1/1,154,000 alleles

Overall 7.16e-05% 1/1,397,396 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.Ser134Phe
Coding: c.401C>T
MANE Select: NM_002356
Type: single nucleotide variant
Location: chr6:113859981 (GRCh38)
Gene constraint: LOEUF 1.86 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.42 · 1 PDB
Residue 134: 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.Ala217Val 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-ser134phe (accessed [today's date]).

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