Is MARK4 p.Phe104Leu (c.312C>G) pathogenic?

MARK4 p.Phe104Leu (c.312C>G) is classified Uncertain significance in MARK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-24). AlphaMissense: likely pathogenic (0.9915); Very rare (popmax 0.000169%, nfe).

How common is MARK4 p.Phe104Leu (c.312C>G) in the general population?

MARK4 p.Phe104Leu (c.312C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about MARK4 p.Phe104Leu (c.312C>G)?

AlphaMissense predicts likely pathogenic (score 0.9915) — an in-silico prediction, not a clinical call.

MARK4 p.Phe104Leu

c.312C>G · rs1274946963 · VCV2478474

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9915 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9915	likely pathogenic
REVEL	0.263	benign-leaning
SaProt	LLR -11.08	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -0.96, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 15 kb · p 2.8e-27 · regional, not allelic
Overall
CADD	24.4	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 0.000169% European (non-Finnish) · 2/1,180,020 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,200 alleles · very rare exomes 2/1,461,870 · genomes 0/152,330 · 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.Phe104Leu
Coding: c.312C>G
MANE Select: NM_001199867
dbSNP: rs1274946963
Type: single nucleotide variant
Location: chr19:45263324 (GRCh38)
Gene constraint: LOEUF 0.361 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.97 · 2 PDB
Residue 104: the protein kinase 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-phe104leu (accessed [today's date]).

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