Is TRIOBP p.Pro89Ala (c.265C>G) pathogenic?

TRIOBP p.Pro89Ala (c.265C>G) is classified Benign/Likely benign in TRIOBP (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0644); Low-frequency (popmax 1.26%, mid); Associated with autosomal recessive nonsyndromic hearing loss 28.

What condition is associated with TRIOBP p.Pro89Ala (c.265C>G)?

TRIOBP p.Pro89Ala (c.265C>G) is associated with autosomal recessive nonsyndromic hearing loss 28 (ClinVar).

How common is TRIOBP p.Pro89Ala (c.265C>G) in the general population?

TRIOBP p.Pro89Ala (c.265C>G) is low-frequency (popmax 1.26%, mid) (gnomAD).

What do computational predictors say about TRIOBP p.Pro89Ala (c.265C>G)?

AlphaMissense predicts likely benign (score 0.0644) — an in-silico prediction, not a clinical call.

TRIOBP p.Pro89Ala

c.265C>G · rs199646135 · VCV165582

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0644 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.26%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 28

Computational evidence

Protein change
AlphaMissense	0.0644	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -6.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.43	GERP -0.46
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.92 · regional, not allelic
Overall
CADD	15.15	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 1.26% Middle Eastern · 76/6,052 alleles

Filtering AF 1.03% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.945%

Overall 0.461% 7,444/1,613,514 alleles · low-frequency exomes 6,871/1,461,330 · genomes 573/152,184 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.26%	80
Ashkenazi Jewishnot grpmax-eligible	1.2%	83
European (non-Finnish)	0.53%	189
Remaining individualsnot grpmax-eligible	0.525%	190
Admixed American	0.402%	249
South Asian	0.144%	695
African / African-American	0.0573%	1,744
Finnishnot grpmax-eligible	0.0251%	3,992

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.Pro89Ala
Coding: c.265C>G
MANE Select: NM_001039141
dbSNP: rs199646135
Type: single nucleotide variant
Location: chr22:37713220 (GRCh38)
Gene constraint: LOEUF 0.865 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 40.77
Residue 89: 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-pro89ala (accessed [today's date]).

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