Is TRRAP p.Pro2199Leu (c.6596C>T) pathogenic?

TRRAP p.Pro2199Leu (c.6596C>T) is classified Conflicting classifications of pathogenicity in TRRAP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-18). AlphaMissense: likely benign (0.1709); Very rare (popmax 0.00356%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TRRAP p.Pro2199Leu (c.6596C>T)?

TRRAP p.Pro2199Leu (c.6596C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TRRAP p.Pro2199Leu (c.6596C>T) in the general population?

TRRAP p.Pro2199Leu (c.6596C>T) is very rare (popmax 0.00356%, nfe) (gnomAD).

What do computational predictors say about TRRAP p.Pro2199Leu (c.6596C>T)?

AlphaMissense predicts likely benign (score 0.1709) — an in-silico prediction, not a clinical call.

TRRAP p.Pro2199Leu

c.6596C>T · rs777582022 · VCV1928725

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1709 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1709	likely benign
REVEL	0.639	indeterminate
SaProt	—	not scored · why
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	24.2	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 P2192L vs ClinVar P2199L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00356% European (non-Finnish) · 42/1,180,050 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00273% 44/1,614,100 alleles · very rare exomes 42/1,461,892 · genomes 2/152,208 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,096
Admixed American	0.00167%	60,006
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Pro2199Leu
Coding: c.6596C>T
MANE Select: NM_001375524
dbSNP: rs777582022
Type: single nucleotide variant
Location: chr7:98961367 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRRAP p.Pro2199Ala Uncertain significance ★ ⚠ same residue
TRRAP c.8247+5G>T Uncertain significance ★★ same condition
TRRAP p.Ala1055Thr Uncertain significance ★★ same condition
TRRAP p.Ala1880Val Uncertain significance ★★ ⚠ same condition
TRRAP p.Ala1895Val Uncertain significance ★★ same condition
TRRAP p.Ala1995Thr Uncertain significance ★★ same condition
TRRAP p.Ala2656Thr Uncertain significance ★★ ⚠ same condition
TRRAP p.Ala322Ser 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/trrap-p-pro2199leu (accessed [today's date]).

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