Is TRIP12 p.Arg1663Lys (c.4988G>A) pathogenic?

TRIP12 p.Arg1663Lys (c.4988G>A) is classified Uncertain significance in TRIP12 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-23). AlphaMissense: likely pathogenic (0.8027); Very rare (popmax 0.00191%, amr).

How common is TRIP12 p.Arg1663Lys (c.4988G>A) in the general population?

TRIP12 p.Arg1663Lys (c.4988G>A) is very rare (popmax 0.00191%, amr) (gnomAD).

What do computational predictors say about TRIP12 p.Arg1663Lys (c.4988G>A)?

AlphaMissense predicts likely pathogenic (score 0.8027) — an in-silico prediction, not a clinical call.

TRIP12 p.Arg1663Lys

c.4988G>A · VCV4960395

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8027 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00191%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8027	likely pathogenic
REVEL	0.24	benign-leaning
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 1,801 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R1588K vs ClinVar R1663K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00191% Admixed American · 1/52,438 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000189% 3/1,589,654 alleles · very rare exomes 3/1,437,582 · genomes 0/152,072 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00191%	52,438
European (non-Finnish)	0.00017%	586,679

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: TRIP12
Protein: p.Arg1663Lys
Coding: c.4988G>A
MANE Select: NM_001348323
Type: single nucleotide variant
Location: chr2:229787512 (GRCh38)
Gene constraint: LOEUF 0.145 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.06 · 5 PDB
Residue 1588 UniProt numbering: the 'k-box' region; an α-helix; a UniProt-annotated variant site (in clabars; uncertain significance); a UniProt-annotated variant site (in clabars)

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

Similar variants

TRIP12 c.3624+1G>A Likely pathogenic ★★ same type
TRIP12 p.Arg1635Gln Pathogenic/Likely pathogenic ★★ same type
TRIP12 p.Arg1635Ter Pathogenic/Likely pathogenic ★★ same type
TRIP12 p.Arg551Ter Pathogenic ★★ same type
TRIP12 p.Gln338Ter Pathogenic ★★ same type
TRIP12 p.Gln689Ter Pathogenic ★★ same type
TRIP12 c.4215+4A>G Uncertain significance ★★ same type
TRIP12 p.Ala1042Val 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/trip12-p-arg1663lys (accessed [today's date]).

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