Is TRRAP p.Pro2199Ala (c.6595C>G) pathogenic?

TRRAP p.Pro2199Ala (c.6595C>G) is classified Uncertain significance in TRRAP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-14). AlphaMissense: likely benign (0.1459); Very rare (popmax 0.00593%, nfe).

How common is TRRAP p.Pro2199Ala (c.6595C>G) in the general population?

TRRAP p.Pro2199Ala (c.6595C>G) is very rare (popmax 0.00593%, nfe) (gnomAD).

What do computational predictors say about TRRAP p.Pro2199Ala (c.6595C>G)?

AlphaMissense predicts likely benign (score 0.1459) — an in-silico prediction, not a clinical call.

TRRAP p.Pro2199Ala

c.6595C>G · VCV4740237

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1459 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00593%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.1459	likely benign
REVEL	0.651	pathogenic-leaning
⇒ REVEL calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 27 kb · p 6.5e-16 · regional, not allelic
Overall
CADD	23.4	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 P2192A vs ClinVar P2199A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00593% European (non-Finnish) · 70/1,180,048 alleles

Filtering AF 0.00478% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00439%

Overall 0.00434% 70/1,614,088 alleles · very rare

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.Pro2199Ala
Coding: c.6595C>G
MANE Select: NM_001375524
Type: single nucleotide variant
Location: chr7:98961366 (GRCh38)
Gene constraint: LOEUF 0.115 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 2199: an α-helix; the 'interaction with tp53' region

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

Similar variants

TRRAP p.Pro2199Leu Conflicting classifications of pathogenicity ★ 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-pro2199ala (accessed [today's date]).

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