Is TRMT1 p.Pro648Ala (c.1942C>G) pathogenic?

TRMT1 p.Pro648Ala (c.1942C>G) is classified Uncertain significance in TRMT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-30). AlphaMissense: likely benign (0.0508); Ultra-rare (popmax 0.0707%, afr); Associated with Inborn genetic diseases.

What condition is associated with TRMT1 p.Pro648Ala (c.1942C>G)?

TRMT1 p.Pro648Ala (c.1942C>G) is associated with Inborn genetic diseases (ClinVar).

How common is TRMT1 p.Pro648Ala (c.1942C>G) in the general population?

TRMT1 p.Pro648Ala (c.1942C>G) is ultra-rare (popmax 0.0707%, afr) (gnomAD).

What do computational predictors say about TRMT1 p.Pro648Ala (c.1942C>G)?

AlphaMissense predicts likely benign (score 0.0508) — an in-silico prediction, not a clinical call.

TRMT1 p.Pro648Ala

c.1942C>G · rs144546583 · VCV2372954

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0508 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0707%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0508	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -5.71	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 0.55	GERP -2.5
Regional constraint	o/e 0.96	unconstrained · MANE · 11 kb · p 0.24 · regional, not allelic
Overall
CADD	1.107	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 0.0707% African / African-American · 53/75,016 alleles

Filtering AF 0.0554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.05%

Overall 0.00397% 64/1,613,856 alleles · ultra-rare exomes 31/1,461,582 · genomes 33/152,274 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0707%	1,415
East Asian	0.00891%	11,220
Admixed American	0.005%	20,008
Remaining individualsnot grpmax-eligible	0.0048%	20,831
European (non-Finnish)	8.47e-05%	1,179,979

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.Pro648Ala
Coding: c.1942C>G
MANE Select: NM_001136035
dbSNP: rs144546583
Type: single nucleotide variant
Location: chr19:13104973 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68 · 1 PDB
Residue 648: the 'disordered' region

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-pro648ala (accessed [today's date]).

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