Is TRIOBP p.Ser699Phe (c.2096C>T) pathogenic?

TRIOBP p.Ser699Phe (c.2096C>T) is classified Uncertain significance in TRIOBP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-09). AlphaMissense: likely benign (0.1788); Ultra-rare (popmax 0.0256%, afr).

How common is TRIOBP p.Ser699Phe (c.2096C>T) in the general population?

TRIOBP p.Ser699Phe (c.2096C>T) is ultra-rare (popmax 0.0256%, afr) (gnomAD).

What do computational predictors say about TRIOBP p.Ser699Phe (c.2096C>T)?

AlphaMissense predicts likely benign (score 0.1788) — an in-silico prediction, not a clinical call.

TRIOBP p.Ser699Phe

c.2096C>T · rs760809501 · VCV2085199

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1788 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0256%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1788	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -10.20	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.039	GERP 0.32
Regional constraint	o/e 0.83	unconstrained · MANE · 468 bp · p 0.019 · regional, not allelic
Overall
CADD	18.67	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0256% African / African-American · 19/74,152 alleles

Filtering AF 0.0167% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0139%

Overall 0.00137% 22/1,610,852 alleles · ultra-rare exomes 12/1,460,132 · genomes 10/150,720 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0256%	3,903
Admixed American	0.00168%	59,628
Remaining individualsnot grpmax-eligible	0.0016%	62,362
European (non-Finnish)	8.48e-05%	1,178,596

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: TRIOBP
Protein: p.Ser699Phe
Coding: c.2096C>T
MANE Select: NM_001039141
dbSNP: rs760809501
Type: single nucleotide variant
Location: chr22:37724652 (GRCh38)
Gene constraint: LOEUF 0.865 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 40.77
Residue 699: the 'disordered' region

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

Similar variants

TRIOBP p.Ser699Thr Uncertain significance ★ ⚠ same residue
TRIOBP c.5184+1G>A Pathogenic/Likely pathogenic ★★ same type
TRIOBP p.Arg1025Ter Pathogenic/Likely pathogenic ★★ same type
TRIOBP p.Arg1068Ter Pathogenic/Likely pathogenic ★★ same type
TRIOBP p.Arg1117Ter Pathogenic ★★ same type
TRIOBP p.Arg1745Ter Likely pathogenic ★★ same type
TRIOBP p.Arg347Ter Pathogenic ★★ same type
TRIOBP p.Arg399Ter Pathogenic/Likely pathogenic ★★ 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/triobp-p-ser699phe (accessed [today's date]).

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