Is TRRAP p.Ser2090Phe (c.6269C>T) pathogenic?

TRRAP p.Ser2090Phe (c.6269C>T) is classified Uncertain significance in TRRAP (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.1432); Very rare (popmax 0.00223%, eas); Associated with developmental delay with or without dysmorphic facies and autism.

What condition is associated with TRRAP p.Ser2090Phe (c.6269C>T)?

TRRAP p.Ser2090Phe (c.6269C>T) is associated with developmental delay with or without dysmorphic facies and autism (ClinVar).

How common is TRRAP p.Ser2090Phe (c.6269C>T) in the general population?

TRRAP p.Ser2090Phe (c.6269C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about TRRAP p.Ser2090Phe (c.6269C>T)?

AlphaMissense predicts likely benign (score 0.1432) — an in-silico prediction, not a clinical call.

TRRAP p.Ser2090Phe

c.6269C>T · rs1584360078 · VCV2585288

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1432 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

developmental delay with or without dysmorphic facies and autism

Computational evidence

Protein change
AlphaMissense	0.1432	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 0.78, phastCons 0.98
Regional constraint	o/e 0.77	unconstrained · MANE · 27 kb · p 6.5e-16 · regional, not allelic
Overall
CADD	22.1	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S2083F vs ClinVar S2090F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,876 alleles

Overall 0.000124% 2/1,614,186 alleles · very rare exomes 2/1,461,884 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,876
European (non-Finnish)	8.47e-05%	1,180,034

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.Ser2090Phe
Coding: c.6269C>T
MANE Select: NM_001375524
dbSNP: rs1584360078
Type: single nucleotide variant
Location: chr7:98958018 (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

developmental delay with or without dysmorphic facies and autism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRRAP p.Ser2090Ala Benign ★ same residue
TRRAP p.Arg1035Gln Pathogenic/Likely pathogenic ★★ same condition
TRRAP p.Glu1104Gly Pathogenic/Likely pathogenic ★★ same condition
TRRAP p.Met3318Val Pathogenic/Likely pathogenic ★★ same condition
TRRAP p.Ala1995Thr Uncertain significance ★★ same condition
TRRAP p.Ala3669Val Uncertain significance ★★ ⚠ same condition
TRRAP p.Ala3764Val Uncertain significance ★★ same condition
TRRAP p.Ala953Thr 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-ser2090phe (accessed [today's date]).

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