Is TRMT1L p.Phe592Leu (c.1774T>C) pathogenic?

TRMT1L p.Phe592Leu (c.1774T>C) is classified Uncertain significance in TRMT1L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely benign (0.2641); Very rare (popmax 0.00722%, amr).

How common is TRMT1L p.Phe592Leu (c.1774T>C) in the general population?

TRMT1L p.Phe592Leu (c.1774T>C) is very rare (popmax 0.00722%, amr) (gnomAD).

What do computational predictors say about TRMT1L p.Phe592Leu (c.1774T>C)?

AlphaMissense predicts likely benign (score 0.2641) — an in-silico prediction, not a clinical call.

TRMT1L p.Phe592Leu

c.1774T>C · VCV4599442

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2641 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00722%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2641	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -4.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 0.39, phastCons 0.98
Regional constraint	o/e 0.84	unconstrained · MANE · 5,079 bp · p 0.016 · regional, not allelic
Overall
CADD	17.4	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 0.00722% Admixed American · 3/41,528 alleles

Filtering AF 0.00192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00103%

Overall 0.000222% 3/1,353,154 alleles · very rare

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: TRMT1L
Protein: p.Phe592Leu
Coding: c.1774T>C
MANE Select: NM_030934
Type: single nucleotide variant
Location: chr1:185123905 (GRCh38)
Gene constraint: LOEUF 0.567 · pLI 0.31 (gnomAD)
Structure: AlphaFold pLDDT 73.62
Residue 592: the trm1 methyltransferase domain

Full TRMT1L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRMT1L p.Ala105Val Uncertain significance ★ ⚠ same type
TRMT1L p.Ala120Pro Uncertain significance ★ ⚠ same type
TRMT1L p.Ala120Thr Uncertain significance ★ ⚠ same type
TRMT1L p.Ala271Ser Uncertain significance ★ ⚠ same type
TRMT1L p.Ala385Ser Uncertain significance ★ ⚠ same type
TRMT1L p.Ala443Ser Uncertain significance ★ ⚠ same type
TRMT1L p.Ala444Thr Uncertain significance ★ ⚠ same type
TRMT1L p.Ala479Thr Uncertain significance ★ ⚠ same type

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/trmt1l-p-phe592leu (accessed [today's date]).

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