Is TRIM59 p.Gln135Pro (c.404A>C) pathogenic?

TRIM59 p.Gln135Pro (c.404A>C) is classified Uncertain significance in TRIM59 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-21). AlphaMissense: likely benign (0.1327); Ultra-rare (popmax 0.0816%, amr).

How common is TRIM59 p.Gln135Pro (c.404A>C) in the general population?

TRIM59 p.Gln135Pro (c.404A>C) is ultra-rare (popmax 0.0816%, amr) (gnomAD).

What do computational predictors say about TRIM59 p.Gln135Pro (c.404A>C)?

AlphaMissense predicts likely benign (score 0.1327) — an in-silico prediction, not a clinical call.

TRIM59 p.Gln135Pro

c.404A>C · rs202041217 · VCV2394981

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1327 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0816%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1327	likely benign
REVEL	0.255	benign-leaning
SaProt	LLR -9.39	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 3.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 1,208 bp · p 0.72 · regional, not allelic
Overall
CADD	24.2	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 0.0816% Admixed American · 49/60,016 alleles

Filtering AF 0.0634% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.057%

Overall 0.00353% 57/1,614,056 alleles · ultra-rare exomes 32/1,461,766 · genomes 25/152,290 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0816%	1,225
Remaining individualsnot grpmax-eligible	0.0096%	10,417
African / African-American	0.00266%	37,525

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: TRIM59
Protein: p.Gln135Pro
Coding: c.404A>C
MANE Select: NM_173084
dbSNP: rs202041217
Type: single nucleotide variant
Location: chr3:160438780 (GRCh38)
Gene constraint: LOEUF 0.675 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 84.52

Full TRIM59 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRIM59 p.Gln135His Uncertain significance ★ ⚠ same residue
TRIM59 p.Arg21His Uncertain significance ★ ⚠ same type
TRIM59 p.Arg60Gly Uncertain significance ★ ⚠ same type
TRIM59 p.Asn215Tyr Uncertain significance ★ ⚠ same type
TRIM59 p.Asn377Ser Uncertain significance ★ ⚠ same type
TRIM59 p.Asn384Ser Uncertain significance ★ ⚠ same type
TRIM59 p.Asp181Tyr Uncertain significance ★ ⚠ same type
TRIM59 p.Asp209Gly 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/trim59-p-gln135pro (accessed [today's date]).

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