Is TRIOBP p.Ser734Phe (c.2201C>T) pathogenic?

TRIOBP p.Ser734Phe (c.2201C>T) is classified Conflicting classifications of pathogenicity in TRIOBP (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-24). AlphaMissense: likely benign (0.2378); Low-frequency (popmax 1.59%, mid); Associated with autosomal recessive nonsyndromic hearing loss 28.

What condition is associated with TRIOBP p.Ser734Phe (c.2201C>T)?

TRIOBP p.Ser734Phe (c.2201C>T) is associated with autosomal recessive nonsyndromic hearing loss 28 (ClinVar).

How common is TRIOBP p.Ser734Phe (c.2201C>T) in the general population?

TRIOBP p.Ser734Phe (c.2201C>T) is low-frequency (popmax 1.59%, mid) (gnomAD).

What do computational predictors say about TRIOBP p.Ser734Phe (c.2201C>T)?

AlphaMissense predicts likely benign (score 0.2378) — an in-silico prediction, not a clinical call.

TRIOBP p.Ser734Phe

c.2201C>T · rs199794705 · VCV290786

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.2378 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.59%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 28

Computational evidence

Protein change
AlphaMissense	0.2378	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -11.75	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 -0.13	GERP 1.6
Regional constraint	o/e 0.83	unconstrained · MANE · 468 bp · p 0.019 · regional, not allelic
Overall
CADD	18.81	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 1.59% Middle Eastern · 96/6,054 alleles

Filtering AF 1.33% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.23%

Overall 0.0659% 1,062/1,612,540 alleles · low-frequency exomes 950/1,460,900 · genomes 112/151,640 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.59%	63
Ashkenazi Jewishnot grpmax-eligible	0.73%	137
Remaining individualsnot grpmax-eligible	0.173%	578
Admixed American	0.0918%	1,090
South Asian	0.0461%	2,168
European (non-Finnish)	0.0442%	2,263
African / African-American	0.0294%	3,397
Finnishnot grpmax-eligible	0.00313%	31,956

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.Ser734Phe
Coding: c.2201C>T
MANE Select: NM_001039141
dbSNP: rs199794705
Type: single nucleotide variant
Location: chr22:37724757 (GRCh38)
Gene constraint: LOEUF 0.865 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 40.77
Residue 734: the 'disordered' region

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

Disease context

autosomal recessive nonsyndromic hearing loss 28 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRIOBP c.5184+1G>A Pathogenic/Likely pathogenic ★★ same condition
TRIOBP p.Arg1025Ter Pathogenic/Likely pathogenic ★★ same condition
TRIOBP p.Arg1068Ter Pathogenic/Likely pathogenic ★★ same condition
TRIOBP p.Arg1117Ter Pathogenic ★★ same condition
TRIOBP p.Arg1745Ter Likely pathogenic ★★ same condition
TRIOBP p.Arg347Ter Pathogenic ★★ same condition
TRIOBP p.Arg399Ter Pathogenic/Likely pathogenic ★★ same condition
TRIOBP p.Arg448Ter Pathogenic ★★ 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/triobp-p-ser734phe (accessed [today's date]).

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