Is TRIP4 p.Pro389Ser (c.1165C>T) pathogenic?

TRIP4 p.Pro389Ser (c.1165C>T) is classified Conflicting classifications of pathogenicity in TRIP4 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-04-17). AlphaMissense: ambiguous (0.5375); Ultra-rare (popmax 0.089%, sas); Associated with Inborn genetic diseases.

What condition is associated with TRIP4 p.Pro389Ser (c.1165C>T)?

TRIP4 p.Pro389Ser (c.1165C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TRIP4 p.Pro389Ser (c.1165C>T) in the general population?

TRIP4 p.Pro389Ser (c.1165C>T) is ultra-rare (popmax 0.089%, sas) (gnomAD).

What do computational predictors say about TRIP4 p.Pro389Ser (c.1165C>T)?

AlphaMissense predicts ambiguous (score 0.5375) — an in-silico prediction, not a clinical call.

TRIP4 p.Pro389Ser

c.1165C>T · rs144077712 · VCV1188593

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.5375 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.089%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5375	ambiguous
REVEL	0.287	benign-leaning
SaProt	LLR -5.31	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 67 kb · p 0.41 · regional, not allelic
Overall
CADD	23.9	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 0.089% South Asian · 81/91,056 alleles

Filtering AF 0.0733% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0675%

Overall 0.0618% 997/1,613,836 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.089%	1,124
Remaining individualsnot grpmax-eligible	0.0816%	1,225
European (non-Finnish)	0.0721%	1,387
Middle Eastern	0.0164%	6,082
African / African-American	0.0107%	9,362
Admixed American	0.00667%	14,995
East Asian	0.00223%	44,884

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.Pro389Ser
Coding: c.1165C>T
MANE Select: NM_016213
dbSNP: rs144077712
Type: single nucleotide variant
Location: chr15:64414206 (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 389: the 'mediates interaction with ufl1' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRIP4 p.Ala398Thr Uncertain significance ★★ ⚠ same condition
TRIP4 p.Arg104Gln Uncertain significance ★★ ⚠ same condition
TRIP4 p.Arg189Cys Uncertain significance ★★ ⚠ same condition
TRIP4 p.Arg321Gln Uncertain significance ★★ ⚠ same condition
TRIP4 p.Arg492Cys Uncertain significance ★★ ⚠ same condition
TRIP4 p.Asp100Asn Uncertain significance ★★ ⚠ same condition
TRIP4 p.Asp501Glu Uncertain significance ★★ ⚠ same condition
TRIP4 p.Gln441Leu Uncertain significance ★★ ⚠ same condition

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-pro389ser (accessed [today's date]).

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