Is MARK4 p.Glu327Lys (c.979G>A) pathogenic?

MARK4 p.Glu327Lys (c.979G>A) is classified Uncertain significance in MARK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-25). AlphaMissense: likely benign (0.2942); Very rare (popmax 0.0011%, sas).

How common is MARK4 p.Glu327Lys (c.979G>A) in the general population?

MARK4 p.Glu327Lys (c.979G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about MARK4 p.Glu327Lys (c.979G>A)?

AlphaMissense predicts likely benign (score 0.2942) — an in-silico prediction, not a clinical call.

MARK4 p.Glu327Lys

c.979G>A · VCV4051845

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2942 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2942	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -10.53	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.5	GERP 0.009, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 24 kb · p 0.0023 · regional, not allelic
Overall
CADD	29.2	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 0.0011% South Asian · 1/91,072 alleles

Overall 6.2e-05% 1/1,613,898 alleles · very rare exomes 1/1,461,680 · genomes 0/152,218 · joint denominator

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.Glu327Lys
Coding: c.979G>A
MANE Select: NM_001199867
Type: single nucleotide variant
Location: chr19:45278588 (GRCh38)
Gene constraint: LOEUF 0.361 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.97 · 2 PDB
Residue 327: the uba domain; an α-helix

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-glu327lys (accessed [today's date]).

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