Is MLX p.Ile233Ser (c.698T>G) pathogenic?

MLX p.Ile233Ser (c.698T>G) is classified Uncertain significance in MLX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely benign (0.1127); Rare (popmax 0.154%, eas).

How common is MLX p.Ile233Ser (c.698T>G) in the general population?

MLX p.Ile233Ser (c.698T>G) is rare (popmax 0.154%, eas) (gnomAD).

What do computational predictors say about MLX p.Ile233Ser (c.698T>G)?

AlphaMissense predicts likely benign (score 0.1127) — an in-silico prediction, not a clinical call.

MLX p.Ile233Ser

c.698T>G · rs762127321 · VCV2602649

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1127 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.154%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1127	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -5.61	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,475 bp · p 0.22 · regional, not allelic
Overall
CADD	24.3	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I287S vs ClinVar I233S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.154% East Asian · 69/44,882 alleles

Filtering AF 0.125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.114%

Overall 0.00446% 72/1,614,230 alleles · rare exomes 67/1,461,876 · genomes 5/152,354 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.154%	650
Admixed American	0.00333%	30,012
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Ile233Ser
Coding: c.698T>G
MANE Select: NM_198204
dbSNP: rs762127321
Type: single nucleotide variant
Location: chr17:42571566 (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-ile233ser (accessed [today's date]).

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