Is TRMT5 p.Ala435Val (c.1304C>T) pathogenic?

TRMT5 p.Ala435Val (c.1304C>T) is classified Uncertain significance in TRMT5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-25). AlphaMissense: likely benign (0.1199); Very rare (popmax 0.0011%, sas).

How common is TRMT5 p.Ala435Val (c.1304C>T) in the general population?

TRMT5 p.Ala435Val (c.1304C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about TRMT5 p.Ala435Val (c.1304C>T)?

AlphaMissense predicts likely benign (score 0.1199) — an in-silico prediction, not a clinical call.

TRMT5 p.Ala435Val

c.1304C>T · rs772546731 · VCV2010678

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1199 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1199	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -6.77	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 5.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 5,861 bp · p 0.27 · regional, not allelic
Overall
CADD	18.87	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 0.0011% South Asian · 1/91,082 alleles

Overall 6.2e-05% 1/1,614,134 alleles · very rare exomes 1/1,461,886 · genomes 0/152,248 · joint denominator

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: TRMT5
Protein: p.Ala435Val
Coding: c.1304C>T
MANE Select: NM_020810
dbSNP: rs772546731
Type: single nucleotide variant
Location: chr14:60975615 (GRCh38)
Gene constraint: LOEUF 0.969 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.50

Full TRMT5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRMT5 p.Ala188Asp Uncertain significance ★★ ⚠ same type
TRMT5 p.Ala45Thr Uncertain significance ★★ ⚠ same type
TRMT5 p.Ala45Val Uncertain significance ★★ ⚠ same type
TRMT5 p.Arg120Cys Uncertain significance ★★ ⚠ same type
TRMT5 p.Arg125His Uncertain significance ★★ ⚠ same type
TRMT5 p.Arg15Thr Uncertain significance ★★ ⚠ same type
TRMT5 p.Arg266Gln Uncertain significance ★★ ⚠ same type
TRMT5 p.Arg291His 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/trmt5-p-ala435val (accessed [today's date]).

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