Is TRIM4 p.Pro292Ser (c.874C>T) pathogenic?

TRIM4 p.Pro292Ser (c.874C>T) is classified Uncertain significance in TRIM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-31). AlphaMissense: likely benign (0.212); Very rare (popmax 0.000763%, nfe).

How common is TRIM4 p.Pro292Ser (c.874C>T) in the general population?

TRIM4 p.Pro292Ser (c.874C>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about TRIM4 p.Pro292Ser (c.874C>T)?

AlphaMissense predicts likely benign (score 0.212) — an in-silico prediction, not a clinical call.

TRIM4 p.Pro292Ser

c.874C>T · rs267601667 · VCV3810431

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.212 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.212	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -8.65	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 1.6	GERP 0.09, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 17 kb · p 0.012 · regional, not allelic
Overall
CADD	18.84	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P318S vs ClinVar P292S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,179,994 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,613,634 alleles · very rare exomes 8/1,461,456 · genomes 1/152,178 · 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: TRIM4
Protein: p.Pro292Ser
Coding: c.874C>T
MANE Select: NM_033091
dbSNP: rs267601667
Type: single nucleotide variant
Location: chr7:99892714 (GRCh38)
Gene constraint: LOEUF 1.353 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.42
Residue 318 UniProt numbering: the b30.2/spry domain

Full TRIM4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRIM4 p.Pro292Ala Uncertain significance ★ ⚠ same residue
TRIM4 p.Ala119Thr Uncertain significance ★ ⚠ same type
TRIM4 p.Ala121Thr Uncertain significance ★ ⚠ same type
TRIM4 p.Ala159Thr Uncertain significance ★ ⚠ same type
TRIM4 p.Arg103Gln Uncertain significance ★ ⚠ same type
TRIM4 p.Arg139Gly Uncertain significance ★ ⚠ same type
TRIM4 p.Arg139His Uncertain significance ★ ⚠ same type
TRIM4 p.Arg139Leu 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/trim4-p-pro292ser (accessed [today's date]).

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