Is TRRAP p.Phe527= (c.1581C>T) pathogenic?

TRRAP p.Phe527= (c.1581C>T) is classified Likely benign in TRRAP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-05). Very rare (popmax 0.00822%, nfe).

How common is TRRAP p.Phe527= (c.1581C>T) in the general population?

TRRAP p.Phe527= (c.1581C>T) is very rare (popmax 0.00822%, nfe) (gnomAD).

TRRAP p.Phe527=

c.1581C>T · rs138096391 · VCV2177740

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00822%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.462	indeterminate
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.50 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.92	GERP -1.7, phastCons 1
Overall
CADD	9.386	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00822% European (non-Finnish) · 97/1,179,342 alleles

Filtering AF 0.00689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00634%

Overall 0.00705% 113/1,603,596 alleles · very rare exomes 105/1,453,884 · genomes 8/149,712 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0107%	9,344
European (non-Finnish)grpmax	0.00822%	12,158
South Asian	0.0066%	15,149
East Asian	0.00223%	44,762
Admixed American	0.00168%	59,580
Remaining individualsnot grpmax-eligible	0.0016%	62,358
African / African-American	0.00135%	74,036

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe527=
Coding: c.1581C>T
MANE Select: NM_001375524
dbSNP: rs138096391
Type: single nucleotide variant
Location: chr7:98910286 (GRCh38)
Gene constraint: LOEUF 0.115 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 527: the 'disordered' region

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

Similar variants

TRRAP p.Phe527_Glu528insValProProPhe 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-phe527 (accessed [today's date]).

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