Is TRMU p.Pro318= (c.954C>T) pathogenic?

TRMU p.Pro318= (c.954C>T) is classified Conflicting classifications of pathogenicity in TRMU (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-03). Ultra-rare (popmax 0.0143%, sas); Associated with acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins.

How common is TRMU p.Pro318= (c.954C>T) in the general population?

TRMU p.Pro318= (c.954C>T) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

TRMU p.Pro318=

Q: What condition is associated with TRMU p.Pro318= (c.954C>T)?

TRMU p.Pro318= (c.954C>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.954C>T · rs758271660 · VCV500143

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

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 -15	GERP -3
Overall
CADD	0.02	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0143% South Asian · 13/91,094 alleles

Filtering AF 0.00844% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.00322% 52/1,613,148 alleles · ultra-rare exomes 51/1,460,956 · genomes 1/152,192 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	7,007
Admixed American	0.00333%	30,002
Remaining individualsnot grpmax-eligible	0.0032%	31,239
European (non-Finnish)	0.0028%	35,759
East Asian	0.00223%	44,876
African / African-American	0.00133%	74,932

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.Pro318=
Coding: c.954C>T
MANE Select: NM_018006
dbSNP: rs758271660
Type: single nucleotide variant
Location: chr22:46355524 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.60

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 p.Pro318Ala Uncertain significance ★★ ⚠ same residue
TRMU p.Pro318Ser Uncertain significance ★★ same residue
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

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-pro318 (accessed [today's date]).

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