Is MARK4 p.Ala462Val (c.1385C>T) pathogenic?

MARK4 p.Ala462Val (c.1385C>T) is classified Uncertain significance in MARK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.0685); Very rare (popmax 0.00683%, eas).

How common is MARK4 p.Ala462Val (c.1385C>T) in the general population?

MARK4 p.Ala462Val (c.1385C>T) is very rare (popmax 0.00683%, eas) (gnomAD).

What do computational predictors say about MARK4 p.Ala462Val (c.1385C>T)?

AlphaMissense predicts likely benign (score 0.0685) — an in-silico prediction, not a clinical call.

MARK4 p.Ala462Val

c.1385C>T · VCV4104159

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0685 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00683%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0685	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -6.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.006	GERP -0.99, phastCons 0.001
Regional constraint	o/e 0.88	unconstrained · MANE · 24 kb · p 0.0023 · regional, not allelic
Overall
CADD	5.411	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 0.00683% East Asian · 3/43,920 alleles

Filtering AF 0.0039% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00357%

Overall 0.00402% 64/1,590,682 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00683%	14,640
European (non-Finnish)	0.00497%	20,123
Ashkenazi Jewishnot grpmax-eligible	0.00346%	28,900
Remaining individualsnot grpmax-eligible	0.00163%	61,320
African / African-American	0.00134%	74,466

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.Ala462Val
Coding: c.1385C>T
MANE Select: NM_001199867
Type: single nucleotide variant
Location: chr19:45287555 (GRCh38)
Gene constraint: LOEUF 0.361 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.97 · 2 PDB
Residue 462: 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.Ala479Thr Uncertain significance ★ ⚠ same type
MARK4 p.Ala47Thr Uncertain significance ★ ⚠ same type
MARK4 p.Ala485Ser 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-ala462val (accessed [today's date]).

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