Is TRMU p.Ala129= (c.387A>G) pathogenic?

TRMU p.Ala129= (c.387A>G) is classified Benign/Likely benign in TRMU (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-04-01). Rare (popmax 0.811%, nfe); Associated with acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins.

How common is TRMU p.Ala129= (c.387A>G) in the general population?

TRMU p.Ala129= (c.387A>G) is rare (popmax 0.811%, nfe) (gnomAD).

TRMU p.Ala129=

Q: What condition is associated with TRMU p.Ala129= (c.387A>G)?

TRMU p.Ala129= (c.387A>G) is associated with acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, deafness, aminoglycoside-induced (ClinVar).

Q: How is Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.387A>G · rs144586525 · VCV137708

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

rare (popmax 0.811%, nfe)

Conditions

acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.1	GERP -2.9
Overall
CADD	0.243	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.811% European (non-Finnish) · 9,572/1,179,632 alleles

Filtering AF 0.798% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.792%

Overall 0.655% 10,569/1,613,662 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.97%	51
European (non-Finnish)grpmax	0.811%	123
Remaining individualsnot grpmax-eligible	0.605%	165
Admixed American	0.398%	251
Finnishnot grpmax-eligible	0.294%	340
Ashkenazi Jewishnot grpmax-eligible	0.182%	548
African / African-American	0.129%	774
Middle Eastern	0.116%	865
South Asian	0.0176%	5,691

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: TRMU
Protein: p.Ala129=
Coding: c.387A>G
MANE Select: NM_018006
dbSNP: rs144586525
Type: single nucleotide variant
Location: chr22:46346453 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.60
Residue 129: a disulfide bond

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

Disease context

acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: deafness, aminoglycoside-induced

For Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TRMU c.1019-1G>A Likely pathogenic ★★ same condition
TRMU c.1102-3C>G Likely pathogenic ★★ same condition
TRMU c.249-2A>G Likely pathogenic ★★ same condition
TRMU c.355+1G>C Likely pathogenic ★★ same condition
TRMU c.355+1G>T Likely pathogenic ★★ same condition
TRMU c.478+1G>A Likely pathogenic ★★ same condition
TRMU c.652-2A>G Likely pathogenic ★★ same condition
TRMU c.706-1G>A Pathogenic ★★ same condition

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/trmu-p-ala129 (accessed [today's date]).

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