Is TRMT1 p.Ser425Leu (c.1274C>T) pathogenic?

TRMT1 p.Ser425Leu (c.1274C>T) is classified Uncertain significance in TRMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-14). AlphaMissense: likely benign (0.1222); Ultra-rare (popmax 0.0121%, sas); Associated with Inborn genetic diseases.

What condition is associated with TRMT1 p.Ser425Leu (c.1274C>T)?

TRMT1 p.Ser425Leu (c.1274C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TRMT1 p.Ser425Leu (c.1274C>T) in the general population?

TRMT1 p.Ser425Leu (c.1274C>T) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about TRMT1 p.Ser425Leu (c.1274C>T)?

AlphaMissense predicts likely benign (score 0.1222) — an in-silico prediction, not a clinical call.

TRMT1 p.Ser425Leu

c.1274C>T · rs149382637 · VCV2283732

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1222 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1222	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -9.17	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 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 11 kb · p 0.24 · regional, not allelic
Overall
CADD	24.3	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 0.0121% South Asian · 11/91,084 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00192% 31/1,613,912 alleles · ultra-rare exomes 27/1,461,798 · genomes 4/152,114 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,280
Admixed American	0.00167%	59,990
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.00144%	69,412
African / African-American	0.00134%	74,898

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.Ser425Leu
Coding: c.1274C>T
MANE Select: NM_001136035
dbSNP: rs149382637
Type: single nucleotide variant
Location: chr19:13109587 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68 · 1 PDB
Residue 425: 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.Ser425= Likely benign ★ same residue
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

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-ser425leu (accessed [today's date]).

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