Is MARCKS p.Pro116Ser (c.346C>T) pathogenic?

MARCKS p.Pro116Ser (c.346C>T) is classified Uncertain significance in MARCKS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-21). AlphaMissense: likely benign (0.1347); Rare (popmax 0.143%, mid).

How common is MARCKS p.Pro116Ser (c.346C>T) in the general population?

MARCKS p.Pro116Ser (c.346C>T) is rare (popmax 0.143%, mid) (gnomAD).

What do computational predictors say about MARCKS p.Pro116Ser (c.346C>T)?

AlphaMissense predicts likely benign (score 0.1347) — an in-silico prediction, not a clinical call.

MARCKS p.Pro116Ser

c.346C>T · VCV3543340

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1347 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.143%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1347	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -6.56	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 6.8	GERP -1.4, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 2,830 bp · p 9e-12 · regional, not allelic
Overall
CADD	19.82	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 0.143% Middle Eastern · 7/4,900 alleles

Filtering AF 0.067% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0475%

Overall 0.00987% 145/1,468,564 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.143%	700
Admixed American	0.0283%	3,538
Remaining individualsnot grpmax-eligible	0.0107%	9,354
European (non-Finnish)	0.00969%	10,315
African / African-American	0.00882%	11,332
South Asian	0.00756%	13,222

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.Pro116Ser
Coding: c.346C>T
MANE Select: NM_002356
Type: single nucleotide variant
Location: chr6:113859926 (GRCh38)
Gene constraint: LOEUF 1.86 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.42 · 1 PDB
Residue 116: the 'disordered' region

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

Similar variants

MARCKS p.Pro116Ala Uncertain significance ★ ⚠ same residue
MARCKS p.Pro116Arg Uncertain significance ★ ⚠ same residue
MARCKS p.Pro116Thr Uncertain significance ★ ⚠ same residue
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

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-pro116ser (accessed [today's date]).

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