Is TRMT1 p.Leu165Val (c.493C>G) pathogenic?

TRMT1 p.Leu165Val (c.493C>G) is classified Uncertain significance in TRMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-06). AlphaMissense: ambiguous (0.5266); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TRMT1 p.Leu165Val (c.493C>G)?

TRMT1 p.Leu165Val (c.493C>G) is associated with Inborn genetic diseases (ClinVar).

How common is TRMT1 p.Leu165Val (c.493C>G) in the general population?

TRMT1 p.Leu165Val (c.493C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TRMT1 p.Leu165Val (c.493C>G)?

AlphaMissense predicts ambiguous (score 0.5266) — an in-silico prediction, not a clinical call.

TRMT1 p.Leu165Val

c.493C>G · VCV3810802

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5266 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5266	ambiguous
REVEL	0.401	indeterminate
SaProt	LLR -11.97	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.43 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.3	GERP -0.78, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 11 kb · p 0.24 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TRMT1
Protein: p.Leu165Val
Coding: c.493C>G
MANE Select: NM_001136035
Type: single nucleotide variant
Location: chr19:13115427 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68 · 1 PDB
Residue 165: 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-leu165val (accessed [today's date]).

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