Is TRMT1 p.Arg528fs (c.1581del) pathogenic?

TRMT1 p.Arg528fs (c.1581del) is classified Conflicting classifications of pathogenicity in TRMT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-16). Very rare (popmax 0.00508%, amr); Associated with intellectual developmental disorder, autosomal recessive 68.

What condition is associated with TRMT1 p.Arg528fs (c.1581del)?

TRMT1 p.Arg528fs (c.1581del) is associated with intellectual developmental disorder, autosomal recessive 68 (ClinVar).

How common is TRMT1 p.Arg528fs (c.1581del) in the general population?

TRMT1 p.Arg528fs (c.1581del) is very rare (popmax 0.00508%, amr) (gnomAD).

TRMT1 p.Arg528fs

c.1581del · VCV3573517

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00508%, amr)

Conditions

intellectual developmental disorder, autosomal recessive 68

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 14 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6	GERP 1.2, phastCons 1
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00508% Admixed American · 3/59,102 alleles

Filtering AF 0.00135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000673%

Overall 0.000749% 12/1,601,736 alleles · very rare exomes 8/1,449,472 · genomes 4/152,264 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00508%	19,701
Finnishnot grpmax-eligible	0.00317%	31,512
European (non-Finnish)	0.000597%	167,575

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.Arg528fs
Coding: c.1581del
MANE Select: NM_001136035
Type: Deletion
Location: chr19:13107576 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.68 · 1 PDB

Full TRMT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual developmental disorder, autosomal recessive 68 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRMT1 p.Gln219fs Pathogenic ★★ same condition
TRMT1 p.Lys130fs Likely pathogenic ★★ same condition
TRMT1 p.Tyr445fs Pathogenic ★★ same condition
TRMT1 c.759del Likely pathogenic ★ same condition
TRMT1 p.Leu10fs Likely pathogenic ★ same condition
TRMT1 p.Lys105fs Pathogenic ★ same condition
TRMT1 p.Phe12fs Likely pathogenic ★ same condition
TRMT1 p.Pro238fs Pathogenic ★ 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-arg528fs (accessed [today's date]).

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