Is TRMU p.Pro97Ser (c.289C>T) pathogenic?

TRMU p.Pro97Ser (c.289C>T) is classified Uncertain significance in TRMU (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-11-06). AlphaMissense: likely pathogenic (0.7809); Ultra-rare (popmax 0.0495%, mid); Associated with acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins.

How common is TRMU p.Pro97Ser (c.289C>T) in the general population?

TRMU p.Pro97Ser (c.289C>T) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about TRMU p.Pro97Ser (c.289C>T)?

AlphaMissense predicts likely pathogenic (score 0.7809) — an in-silico prediction, not a clinical call.

TRMU p.Pro97Ser

Q: What condition is associated with TRMU p.Pro97Ser (c.289C>T)?

TRMU p.Pro97Ser (c.289C>T) is associated with acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (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.289C>T · rs886042713 · VCV283815

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7809 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.7809	likely pathogenic
REVEL	0.914	moderately pathogenic-leaning
SaProt	LLR -14.30	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.4	GERP 1.3, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 21 kb · p 0.086 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0495% Middle Eastern · 3/6,062 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.00031% 5/1,613,820 alleles · ultra-rare exomes 5/1,461,796 · genomes 0/152,024 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0016%	62,498
South Asian	0.0011%	91,070

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.Pro97Ser
Coding: c.289C>T
MANE Select: NM_018006
dbSNP: rs886042713
Type: single nucleotide variant
Location: chr22:46343302 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.60
Residue 97: the 'interaction with target base in trna' region

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

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.652-2A>G Likely pathogenic ★★ same condition
TRMU c.706-1G>A Pathogenic ★★ same condition
TRMU c.706-2A>G Pathogenic/Likely 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-pro97ser (accessed [today's date]).

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