Is MLX p.Thr48Ala (c.142A>G) pathogenic?

MLX p.Thr48Ala (c.142A>G) is classified Uncertain significance in MLX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-21). AlphaMissense: ambiguous (0.3504); Very rare (popmax 0.00667%, amr).

How common is MLX p.Thr48Ala (c.142A>G) in the general population?

MLX p.Thr48Ala (c.142A>G) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about MLX p.Thr48Ala (c.142A>G)?

AlphaMissense predicts ambiguous (score 0.3504) — an in-silico prediction, not a clinical call.

MLX p.Thr48Ala

c.142A>G · VCV3873618

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3504 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Computational evidence

Protein change
AlphaMissense	0.3504	ambiguous
REVEL	0.356	indeterminate
SaProt	LLR -7.11	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,475 bp · p 0.22 · regional, not allelic
Overall
CADD	24.5	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 T102A vs ClinVar T48A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,982 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000248% 4/1,613,702 alleles · very rare exomes 4/1,461,682 · genomes 0/152,020 · 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: MLX
Protein: p.Thr48Ala
Coding: c.142A>G
MANE Select: NM_198204
Type: single nucleotide variant
Location: chr17:42568532 (GRCh38)
Gene constraint: LOEUF 0.694 · pLI 0.08 (gnomAD)
Structure: AlphaFold pLDDT 73.71
Residue 102 UniProt numbering: the 'disordered' region

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-thr48ala (accessed [today's date]).

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