Is TRIP4 p.Ser243Cys (c.728C>G) pathogenic?

TRIP4 p.Ser243Cys (c.728C>G) is classified Uncertain significance in TRIP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely benign (0.0761); Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with TRIP4 p.Ser243Cys (c.728C>G)?

TRIP4 p.Ser243Cys (c.728C>G) is associated with Inborn genetic diseases (ClinVar).

How common is TRIP4 p.Ser243Cys (c.728C>G) in the general population?

TRIP4 p.Ser243Cys (c.728C>G) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about TRIP4 p.Ser243Cys (c.728C>G)?

AlphaMissense predicts likely benign (score 0.0761) — an in-silico prediction, not a clinical call.

TRIP4 p.Ser243Cys

c.728C>G · VCV4633645

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0761 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0761	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -8.28	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 0.78	GERP 0.94, phastCons 0.36
Regional constraint	o/e 0.97	unconstrained · MANE · 67 kb · p 0.41 · regional, not allelic
Overall
CADD	18.18	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 0.0107% African / African-American · 8/74,938 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000496% 8/1,614,024 alleles · ultra-rare exomes 3/1,461,806 · genomes 5/152,218 · 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.Ser243Cys
Coding: c.728C>G
MANE Select: NM_016213
Type: single nucleotide variant
Location: chr15:64406360 (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 243: the 'mediates interaction with ddrgk1' 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-ser243cys (accessed [today's date]).

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