Is TRMT1 p.Pro366Leu (c.1097C>T) pathogenic?

TRMT1 p.Pro366Leu (c.1097C>T) is classified Uncertain significance in TRMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-29). AlphaMissense: likely benign (0.074); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with TRMT1 p.Pro366Leu (c.1097C>T)?

TRMT1 p.Pro366Leu (c.1097C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TRMT1 p.Pro366Leu (c.1097C>T) in the general population?

TRMT1 p.Pro366Leu (c.1097C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TRMT1 p.Pro366Leu (c.1097C>T)?

AlphaMissense predicts likely benign (score 0.074) — an in-silico prediction, not a clinical call.

TRMT1 p.Pro366Leu

c.1097C>T · rs1225533183 · VCV2228110

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.074 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.074	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -7.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP 1.4, phastCons 0.96
Regional constraint	o/e 0.96	unconstrained · MANE · 11 kb · p 0.24 · regional, not allelic
Overall
CADD	15.93	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,022 alleles

Overall 0.000124% 2/1,614,048 alleles · very rare exomes 2/1,461,770 · genomes 0/152,278 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Admixed Americangrpmax	0.00167%	60,022

Ashkenazi Jewish 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: TRMT1
Protein: p.Pro366Leu
Coding: c.1097C>T
MANE Select: NM_001136035
dbSNP: rs1225533183
Type: single nucleotide variant
Location: chr19:13109924 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68 · 1 PDB
Residue 366: the trm1 methyltransferase domain

Full TRMT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRMT1 p.Ala337Thr Uncertain significance ★★ ⚠ same condition
TRMT1 p.Ala343Val Uncertain significance ★★ ⚠ same condition
TRMT1 p.Arg358His Uncertain significance ★★ ⚠ same condition
TRMT1 p.Arg410Cys Uncertain significance ★★ ⚠ same condition
TRMT1 p.Asp449Asn Uncertain significance ★★ ⚠ same condition
TRMT1 p.Gly352Arg Uncertain significance ★★ ⚠ same condition
TRMT1 p.Gly42Glu Uncertain significance ★★ ⚠ same condition
TRMT1 p.Leu463Arg Uncertain significance ★★ ⚠ 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/trmt1-p-pro366leu (accessed [today's date]).

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