Is TRRAP p.Thr489Ser (c.1466C>G) pathogenic?

TRRAP p.Thr489Ser (c.1466C>G) is classified Uncertain significance in TRRAP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-24). AlphaMissense: likely benign (0.0712); Very rare (popmax 0.00585%, nfe).

How common is TRRAP p.Thr489Ser (c.1466C>G) in the general population?

TRRAP p.Thr489Ser (c.1466C>G) is very rare (popmax 0.00585%, nfe) (gnomAD).

What do computational predictors say about TRRAP p.Thr489Ser (c.1466C>G)?

AlphaMissense predicts likely benign (score 0.0712) — an in-silico prediction, not a clinical call.

TRRAP p.Thr489Ser

c.1466C>G · rs140514468 · VCV2078076

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0712 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00585%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0712	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.95, phastCons 0.78
Regional constraint	o/e 0.92	unconstrained · MANE · 293 bp · p 0.39 · regional, not allelic
Overall
CADD	19.56	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00585% European (non-Finnish) · 69/1,179,516 alleles

Filtering AF 0.0047% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00431%

Overall 0.00447% 72/1,611,800 alleles · very rare exomes 67/1,459,672 · genomes 5/152,128 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00585%	17,094
Remaining individualsnot grpmax-eligible	0.00481%	20,810

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: TRRAP
Protein: p.Thr489Ser
Coding: c.1466C>G
MANE Select: NM_001375524
dbSNP: rs140514468
Type: single nucleotide variant
Location: chr7:98910171 (GRCh38)
Gene constraint: LOEUF 0.115 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)

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

Similar variants

TRRAP p.Thr489= Likely benign ★★ same residue
TRRAP p.Arg1035Gln Pathogenic/Likely pathogenic ★★ same type
TRRAP p.Glu1104Gly Pathogenic/Likely pathogenic ★★ same type
TRRAP p.Glu1106Lys Likely pathogenic ★★ same type
TRRAP p.Met3318Val Pathogenic/Likely pathogenic ★★ same type
TRRAP p.Val1030Ile Likely pathogenic ★★ same type
TRRAP c.2622+3A>G Uncertain significance ★★ same type
TRRAP c.7176+4A>G 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/trrap-p-thr489ser (accessed [today's date]).

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