Is MARK3 p.Arg680His (c.2039G>A) pathogenic?

MARK3 p.Arg680His (c.2039G>A) is classified Uncertain significance in MARK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.2503); Very rare (popmax 0.00333%, amr).

How common is MARK3 p.Arg680His (c.2039G>A) in the general population?

MARK3 p.Arg680His (c.2039G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about MARK3 p.Arg680His (c.2039G>A)?

AlphaMissense predicts likely benign (score 0.2503) — an in-silico prediction, not a clinical call.

MARK3 p.Arg680His

c.2039G>A · VCV4104150

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2503 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2503	likely benign
REVEL	0.695	pathogenic-leaning
SaProt	LLR -12.97	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.81, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 37 kb · p 0.031 · regional, not allelic
Overall
CADD	31.0	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 0.00333% Admixed American · 2/60,006 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000558% 9/1,614,130 alleles · very rare exomes 7/1,461,888 · genomes 2/152,242 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,003
East Asian	0.00223%	44,904
European (non-Finnish)	0.000508%	196,676

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.Arg680His
Coding: c.2039G>A
MANE Select: NM_001128918
Type: single nucleotide variant
Location: chr14:103503004 (GRCh38)
Gene constraint: LOEUF 0.73 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.25 · 14 PDB

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-arg680his (accessed [today's date]).

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