Is MARK3 p.Pro467Ser (c.1399C>T) pathogenic?

MARK3 p.Pro467Ser (c.1399C>T) is classified Uncertain significance in MARK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-04). AlphaMissense: likely benign (0.0954); Ultra-rare (popmax 0.0267%, afr).

How common is MARK3 p.Pro467Ser (c.1399C>T) in the general population?

MARK3 p.Pro467Ser (c.1399C>T) is ultra-rare (popmax 0.0267%, afr) (gnomAD).

What do computational predictors say about MARK3 p.Pro467Ser (c.1399C>T)?

AlphaMissense predicts likely benign (score 0.0954) — an in-silico prediction, not a clinical call.

MARK3 p.Pro467Ser

c.1399C>T · VCV4051834

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0954 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0954	likely benign
REVEL	0.511	indeterminate
SaProt	LLR -5.95	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 37 kb · p 0.031 · regional, not allelic
Overall
CADD	24.1	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 0.0267% African / African-American · 20/75,046 alleles

Filtering AF 0.0176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00186% 30/1,614,146 alleles · ultra-rare exomes 15/1,461,830 · genomes 15/152,316 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0267%	3,752
Admixed American	0.0117%	8,573
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)	0.000169%	590,005

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: MARK3
Protein: p.Pro467Ser
Coding: c.1399C>T
MANE Select: NM_001128918
Type: single nucleotide variant
Location: chr14:103475127 (GRCh38)
Gene constraint: LOEUF 0.73 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.25 · 14 PDB
Residue 467: the 'disordered' region

Full MARK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MARK3 c.413-4A>G Benign ★★ same type
MARK3 c.1917-11A>G Uncertain significance ★ same type
MARK3 p.Ala373Ser Uncertain significance ★ ⚠ same type
MARK3 p.Ala481Gly Uncertain significance ★ ⚠ same type
MARK3 p.Ala739Val Uncertain significance ★ ⚠ same type
MARK3 p.Ala748Asp Uncertain significance ★ ⚠ same type
MARK3 p.Arg262Lys Uncertain significance ★ ⚠ same type
MARK3 p.Arg305Lys 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/mark3-p-pro467ser (accessed [today's date]).

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