Is MARK4 p.Ala389Val (c.1166C>T) pathogenic?

MARK4 p.Ala389Val (c.1166C>T) is classified Uncertain significance in MARK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-15). AlphaMissense: likely benign (0.091); Ultra-rare (popmax 0.0154%, sas).

How common is MARK4 p.Ala389Val (c.1166C>T) in the general population?

MARK4 p.Ala389Val (c.1166C>T) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about MARK4 p.Ala389Val (c.1166C>T)?

AlphaMissense predicts likely benign (score 0.091) — an in-silico prediction, not a clinical call.

MARK4 p.Ala389Val

c.1166C>T · rs779413121 · VCV3123676

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.091 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.091	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -7.56	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 1.1	GERP 1.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 24 kb · p 0.0023 · regional, not allelic
Overall
CADD	20.9	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 0.0154% South Asian · 14/91,076 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00155% 25/1,613,920 alleles · ultra-rare exomes 22/1,461,816 · genomes 3/152,104 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,505
Admixed American	0.005%	20,000
African / African-American	0.00267%	37,449
European (non-Finnish)	0.000508%	196,662

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.Ala389Val
Coding: c.1166C>T
MANE Select: NM_001199867
dbSNP: rs779413121
Type: single nucleotide variant
Location: chr19:45280624 (GRCh38)
Gene constraint: LOEUF 0.361 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.97 · 2 PDB
Residue 389: 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.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
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-ala389val (accessed [today's date]).

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