Is TRIP12 p.Ser563Pro (c.1687T>C) pathogenic?

TRIP12 p.Ser563Pro (c.1687T>C) is classified Uncertain significance in TRIP12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-04). AlphaMissense: likely pathogenic (0.9946); Absent from gnomAD v4.1; Associated with Clark-Baraitser syndrome.

What condition is associated with TRIP12 p.Ser563Pro (c.1687T>C)?

TRIP12 p.Ser563Pro (c.1687T>C) is associated with Clark-Baraitser syndrome (ClinVar).

How common is TRIP12 p.Ser563Pro (c.1687T>C) in the general population?

TRIP12 p.Ser563Pro (c.1687T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TRIP12 p.Ser563Pro (c.1687T>C)?

AlphaMissense predicts likely pathogenic (score 0.9946) — an in-silico prediction, not a clinical call.

TRIP12 p.Ser563Pro

c.1687T>C · VCV4076274

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9946 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Clark-Baraitser syndrome

Computational evidence

Protein change
AlphaMissense	0.9946	likely pathogenic
REVEL	0.71	pathogenic-leaning
SaProt	LLR -12.93	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 22 kb · p 1e-23 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 S515P vs ClinVar S563P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TRIP12
Protein: p.Ser563Pro
Coding: c.1687T>C
MANE Select: NM_001348323
Type: single nucleotide variant
Location: chr2:229815143 (GRCh38)
Gene constraint: LOEUF 0.145 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.06 · 5 PDB
Residue 515 UniProt numbering: a UniProt-annotated variant site (in clabars; uncertain significance)

Full TRIP12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Clark-Baraitser syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRIP12 p.Ser563Phe Uncertain significance ★ ⚠ same residue
TRIP12 c.3624+1G>A Likely pathogenic ★★ same condition
TRIP12 p.Arg1635Gln Pathogenic/Likely pathogenic ★★ same condition
TRIP12 p.Arg1635Ter Pathogenic/Likely pathogenic ★★ same condition
TRIP12 p.Arg551Ter Pathogenic ★★ same condition
TRIP12 p.Gln338Ter Pathogenic ★★ same condition
TRIP12 p.Gln689Ter Pathogenic ★★ same condition
TRIP12 p.Ala279Thr 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/trip12-p-ser563pro (accessed [today's date]).

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