Is MLX p.Arg75Trp (c.223C>T) pathogenic?

MLX p.Arg75Trp (c.223C>T) is classified Uncertain significance in MLX (ClinVar, No assertion criteria, 1 submitter; last evaluated 2026-05-12). AlphaMissense: ambiguous (0.4337); Very rare (popmax 0.00221%, sas).

How common is MLX p.Arg75Trp (c.223C>T) in the general population?

MLX p.Arg75Trp (c.223C>T) is very rare (popmax 0.00221%, sas) (gnomAD).

What do computational predictors say about MLX p.Arg75Trp (c.223C>T)?

AlphaMissense predicts ambiguous (score 0.4337) — an in-silico prediction, not a clinical call.

MLX p.Arg75Trp

c.223C>T · rs1263926960 · VCV4886844

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4337 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4337	ambiguous
REVEL	0.775	moderately pathogenic-leaning
SaProt	LLR -12.46	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,475 bp · p 0.22 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R129W vs ClinVar R75W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00221% South Asian · 2/90,684 alleles

Filtering AF 0.000366% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000343% 5/1,459,350 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00221%	45,342
European (non-Finnish)	0.000254%	392,930

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: MLX
Protein: p.Arg75Trp
Coding: c.223C>T
MANE Select: NM_198204
dbSNP: rs1263926960
Type: single nucleotide variant
Location: chr17:42568890 (GRCh38)
Gene constraint: LOEUF 0.694 · pLI 0.08 (gnomAD)
Structure: AlphaFold pLDDT 73.71

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

Similar variants

MLX p.Gln169Arg Benign ★★ same type
PSMC3IP c.*9C>T Benign ★★ same type
MLX p.Arg229Gln Uncertain significance ★ ⚠ same type
MLX p.Arg229Trp Uncertain significance ★ ⚠ same type
MLX p.Arg34Cys Uncertain significance ★ ⚠ same type
MLX p.Asn200Ser Uncertain significance ★ ⚠ same type
MLX p.Gln115His Uncertain significance ★ ⚠ same type
MLX p.Gln140Arg 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/mlx-p-arg75trp (accessed [today's date]).

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