Is TRRAP p.Ser2124Phe (c.6371C>T) pathogenic?

TRRAP p.Ser2124Phe (c.6371C>T) is classified Uncertain significance in TRRAP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-03). AlphaMissense: ambiguous (0.4737); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with TRRAP p.Ser2124Phe (c.6371C>T)?

TRRAP p.Ser2124Phe (c.6371C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TRRAP p.Ser2124Phe (c.6371C>T) in the general population?

TRRAP p.Ser2124Phe (c.6371C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about TRRAP p.Ser2124Phe (c.6371C>T)?

AlphaMissense predicts ambiguous (score 0.4737) — an in-silico prediction, not a clinical call.

TRRAP p.Ser2124Phe

c.6371C>T · VCV3811191

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4737 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4737	ambiguous
REVEL	0.243	benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 27 kb · p 6.5e-16 · regional, not allelic
Overall
CADD	27.1	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 S2117F vs ClinVar S2124F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,062 alleles

Overall 0.000124% 2/1,614,072 alleles · very rare exomes 2/1,461,862 · genomes 0/152,210 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,030
South Asiangrpmax	0.0011%	91,062

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.Ser2124Phe
Coding: c.6371C>T
MANE Select: NM_001375524
Type: single nucleotide variant
Location: chr7:98959372 (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.Ser2124Cys 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-ser2124phe (accessed [today's date]).

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