Is TRIM28 p.Pro425Leu (c.1274C>T) pathogenic?

TRIM28 p.Pro425Leu (c.1274C>T) is classified Likely benign in TRIM28 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-10). AlphaMissense: likely benign (0.1153); Ultra-rare (popmax 0.0424%, eas).

How common is TRIM28 p.Pro425Leu (c.1274C>T) in the general population?

TRIM28 p.Pro425Leu (c.1274C>T) is ultra-rare (popmax 0.0424%, eas) (gnomAD).

What do computational predictors say about TRIM28 p.Pro425Leu (c.1274C>T)?

AlphaMissense predicts likely benign (score 0.1153) — an in-silico prediction, not a clinical call.

TRIM28 p.Pro425Leu

c.1274C>T · VCV3715354

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1153 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0424%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1153	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -7.44	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 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 518 bp · p 0.0087 · regional, not allelic
Overall
CADD	24.0	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 0.0424% East Asian · 19/44,864 alleles

Filtering AF 0.0277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.023%

Overall 0.00143% 23/1,613,958 alleles · ultra-rare exomes 20/1,461,700 · genomes 3/152,258 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0424%	2,361
African / African-American	0.00133%	75,026
South Asian	0.0011%	91,080
European (non-Finnish)	0.000169%	590,005

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: TRIM28
Protein: p.Pro425Leu
Coding: c.1274C>T
MANE Select: NM_005762
Type: single nucleotide variant
Location: chr19:58548543 (GRCh38)
Gene constraint: LOEUF 0.17 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.59 · 10 PDB
Residue 425: the 'disordered' region; a UniProt-annotated variant site (risk factor for wt7)

Full TRIM28 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRIM28 p.Ala537Val Uncertain significance ★★ ⚠ same type
TRIM28 p.Arg412His Uncertain significance ★★ ⚠ same type
TRIM28 p.Arg706Cys Uncertain significance ★★ ⚠ same type
TRIM28 p.Arg767His Uncertain significance ★★ ⚠ same type
TRIM28 p.Arg795Cys Uncertain significance ★★ ⚠ same type
TRIM28 p.Asp231Tyr Uncertain significance ★★ ⚠ same type
TRIM28 p.Glu798Asp Uncertain significance ★★ ⚠ same type
TRIM28 p.Gly735Ala 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/trim28-p-pro425leu (accessed [today's date]).

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