Is TRIP4 p.Arg489fs (c.1460_1463dup) pathogenic?

TRIP4 p.Arg489fs (c.14601463dup) is classified Pathogenic in TRIP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). Very rare (popmax 0.00833%, amr).

How common is TRIP4 p.Arg489fs (c.1460_1463dup) in the general population?

TRIP4 p.Arg489fs (c.1460_1463dup) is very rare (popmax 0.00833%, amr) (gnomAD).

TRIP4 p.Arg489fs

c.1460_1463dup · VCV4690706

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

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 10 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.4	GERP 1.9, phastCons 1
Overall
CADD	34.0	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 0.00833% Admixed American · 5/59,994 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00031% 5/1,614,064 alleles · very rare exomes 4/1,461,858 · genomes 1/152,206 · 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: TRIP4
Protein: p.Arg489fs
Coding: c.1460_1463dup
MANE Select: NM_016213
Type: Duplication
Location: chr15:64424129 (GRCh38)
Gene constraint: LOEUF 0.802 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.54 · 10 PDB
Residue 489: the asch domain; an α-helix

Full TRIP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRIP4 p.Arg489Cys Uncertain significance ★★ ⚠ same residue
TRIP4 p.Arg489His Uncertain significance ★ ⚠ same residue
TRIP4 p.Arg46fs Pathogenic ★★ same type
TRIP4 p.Arg278fs Pathogenic ★ same type
TRIP4 p.Ala397_Ala398insGlyAla Uncertain significance ★ same type
TRIP4 p.Lys572fs Uncertain significance ★ same type
TRIP4 p.Val7_Ser8insAlaGlyAlaVal Uncertain significance ★ same type
TRIP4 c.1043+215dup Likely benign ★ 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/trip4-p-arg489fs (accessed [today's date]).

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