Is TRMT1 p.Pro440Arg (c.1319C>G) pathogenic?

TRMT1 p.Pro440Arg (c.1319C>G) is classified Uncertain significance in TRMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-01). AlphaMissense: likely benign (0.1014); Ultra-rare (popmax 0.0574%, afr); Associated with Inborn genetic diseases.

What condition is associated with TRMT1 p.Pro440Arg (c.1319C>G)?

TRMT1 p.Pro440Arg (c.1319C>G) is associated with Inborn genetic diseases (ClinVar).

How common is TRMT1 p.Pro440Arg (c.1319C>G) in the general population?

TRMT1 p.Pro440Arg (c.1319C>G) is ultra-rare (popmax 0.0574%, afr) (gnomAD).

What do computational predictors say about TRMT1 p.Pro440Arg (c.1319C>G)?

AlphaMissense predicts likely benign (score 0.1014) — an in-silico prediction, not a clinical call.

TRMT1 p.Pro440Arg

c.1319C>G · VCV3810793

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1014 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0574%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1014	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -10.32	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 1.4, phastCons 0.95
Regional constraint	o/e 0.96	unconstrained · MANE · 11 kb · p 0.24 · regional, not allelic
Overall
CADD	19.54	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

Grpmax group 0.0574% African / African-American · 43/74,866 alleles

Filtering AF 0.0437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.039%

Overall 0.00378% 61/1,613,736 alleles · ultra-rare exomes 32/1,461,666 · genomes 29/152,070 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0574%	1,741
Remaining individualsnot grpmax-eligible	0.008%	12,494
Admixed American	0.005%	19,999
European (non-Finnish)	0.000847%	118,000

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.Pro440Arg
Coding: c.1319C>G
MANE Select: NM_001136035
Type: single nucleotide variant
Location: chr19:13109459 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68 · 1 PDB
Residue 440: 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

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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-pro440arg (accessed [today's date]).

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