Is TRRAP p.Thr2139Ser (c.6415A>T) pathogenic?

TRRAP p.Thr2139Ser (c.6415A>T) is classified Uncertain significance in TRRAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-31). AlphaMissense: likely benign (0.103); Very rare (popmax 0.00178%, nfe); Associated with TRRAP-related disorder.

What condition is associated with TRRAP p.Thr2139Ser (c.6415A>T)?

TRRAP p.Thr2139Ser (c.6415A>T) is associated with TRRAP-related disorder (ClinVar).

How common is TRRAP p.Thr2139Ser (c.6415A>T) in the general population?

TRRAP p.Thr2139Ser (c.6415A>T) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about TRRAP p.Thr2139Ser (c.6415A>T)?

AlphaMissense predicts likely benign (score 0.103) — an in-silico prediction, not a clinical call.

TRRAP p.Thr2139Ser

c.6415A>T · rs1324324166 · VCV2636761

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.103 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Conditions

TRRAP-related disorder

Computational evidence

Protein change
AlphaMissense	0.103	likely benign
REVEL	0.343	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 27 kb · p 6.5e-16 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM T2132S vs ClinVar T2139S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00178% European (non-Finnish) · 21/1,180,018 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.0013% 21/1,613,858 alleles · very rare exomes 20/1,461,894 · genomes 1/151,964 · 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: TRRAP
Protein: p.Thr2139Ser
Coding: c.6415A>T
MANE Select: NM_001375524
dbSNP: rs1324324166
Type: single nucleotide variant
Location: chr7:98959416 (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

Disease context

TRRAP-related disorder

Similar variants

TRRAP p.Arg1562Gln Uncertain significance ★★ same condition
TRRAP p.Arg447Gln Uncertain significance ★★ same condition
TRRAP p.Ile3068Val Uncertain significance ★★ ⚠ same condition
TRRAP p.Met3545Ile Uncertain significance ★★ same condition
TRRAP p.Pro3761Leu Uncertain significance ★★ same condition
TRRAP p.Tyr2171Cys Uncertain significance ★★ ⚠ same condition
TRRAP p.Val2020Ile Uncertain significance ★★ same condition
TRRAP p.Ile1031Met Likely pathogenic ★ ⚠ 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/trrap-p-thr2139ser (accessed [today's date]).

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