Is MARK4 p.Arg418His (c.1253G>A) pathogenic?

MARK4 p.Arg418His (c.1253G>A) is classified Uncertain significance in MARK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-12). AlphaMissense: ambiguous (0.4018); Ultra-rare (popmax 0.0165%, mid).

How common is MARK4 p.Arg418His (c.1253G>A) in the general population?

MARK4 p.Arg418His (c.1253G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about MARK4 p.Arg418His (c.1253G>A)?

AlphaMissense predicts ambiguous (score 0.4018) — an in-silico prediction, not a clinical call.

MARK4 p.Arg418His

c.1253G>A · rs755396651 · VCV2622977

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4018 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Computational evidence

Protein change
AlphaMissense	0.4018	ambiguous
REVEL	0.342	indeterminate
SaProt	LLR -7.21	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 24 kb · p 0.0023 · regional, not allelic
Overall
CADD	32.0	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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000681% 11/1,614,130 alleles · ultra-rare exomes 11/1,461,856 · genomes 0/152,274 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
South Asian	0.00439%	22,771
East Asian	0.00223%	44,880
Finnishnot grpmax-eligible	0.00156%	64,036
European (non-Finnish)	0.000339%	294,998

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: MARK4
Protein: p.Arg418His
Coding: c.1253G>A
MANE Select: NM_001199867
dbSNP: rs755396651
Type: single nucleotide variant
Location: chr19:45280711 (GRCh38)
Gene constraint: LOEUF 0.361 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.97 · 2 PDB
Residue 418: a UniProt-annotated variant site (in a colorectal adenocarcinoma sample; somatic mutation); the 'disordered' region

Full MARK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MARK4 p.Leu226= Benign ★★ same type
MARK4 p.Thr461= Benign ★★ same type
MARK4 p.Ala168Ser Uncertain significance ★ ⚠ same type
MARK4 p.Ala389Val Uncertain significance ★ ⚠ same type
MARK4 p.Ala457Val Uncertain significance ★ ⚠ same type
MARK4 p.Ala462Val Uncertain significance ★ ⚠ same type
MARK4 p.Ala479Thr Uncertain significance ★ ⚠ same type
MARK4 p.Ala47Thr 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/mark4-p-arg418his (accessed [today's date]).

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