Is MARK2 p.Arg38His (c.113G>A) pathogenic?

MARK2 p.Arg38His (c.113G>A) is classified Uncertain significance in MARK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-03). AlphaMissense: likely benign (0.2209); Very rare (popmax 0.00668%, eas).

How common is MARK2 p.Arg38His (c.113G>A) in the general population?

MARK2 p.Arg38His (c.113G>A) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about MARK2 p.Arg38His (c.113G>A)?

AlphaMissense predicts likely benign (score 0.2209) — an in-silico prediction, not a clinical call.

MARK2 p.Arg38His

c.113G>A · VCV4549936

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2209 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2209	likely benign
REVEL	0.588	indeterminate
SaProt	LLR -8.73	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 10	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 56 kb · p 0.12 · regional, not allelic
Overall
CADD	32.0	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 0.00668% East Asian · 3/44,894 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000682% 11/1,614,016 alleles · very rare exomes 10/1,461,850 · genomes 1/152,166 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,965
Finnishnot grpmax-eligible	0.00625%	16,006
African / African-American	0.00133%	74,922
European (non-Finnish)	0.000254%	393,337

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: MARK2
Protein: p.Arg38His
Coding: c.113G>A
MANE Select: NM_001039469
Type: single nucleotide variant
Location: chr11:63895217 (GRCh38)
Gene constraint: LOEUF 0.287 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.21 · 5 PDB
Residue 38: the 'disordered' region

Full MARK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MARK2 p.Ala432Thr Uncertain significance ★★ ⚠ same type
MARK2 p.Arg264Ser Uncertain significance ★★ ⚠ same type
MARK2 p.Arg482Ter Uncertain significance ★★ same type
MARK2 c.337+8C>G Likely benign ★★ same type
MARK2 p.Pro459= Benign ★★ same type
MARK2 p.Pro740= Benign ★★ same type
MARK2 p.Ser725= Benign ★★ same type
MARK2 c.1102-1G>C Likely pathogenic ★ 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/mark2-p-arg38his (accessed [today's date]).

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