Is TRIOBP p.Arg2139His (c.6416G>A) pathogenic?

TRIOBP p.Arg2139His (c.6416G>A) is classified Uncertain significance in TRIOBP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-14). AlphaMissense: likely benign (0.1282); Very rare (popmax 0.00269%, afr); Associated with autosomal recessive nonsyndromic hearing loss 28.

What condition is associated with TRIOBP p.Arg2139His (c.6416G>A)?

TRIOBP p.Arg2139His (c.6416G>A) is associated with autosomal recessive nonsyndromic hearing loss 28 (ClinVar).

How common is TRIOBP p.Arg2139His (c.6416G>A) in the general population?

TRIOBP p.Arg2139His (c.6416G>A) is very rare (popmax 0.00269%, afr) (gnomAD).

What do computational predictors say about TRIOBP p.Arg2139His (c.6416G>A)?

AlphaMissense predicts likely benign (score 0.1282) — an in-silico prediction, not a clinical call.

TRIOBP p.Arg2139His

c.6416G>A · VCV3892724

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1282 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00269%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autosomal recessive nonsyndromic hearing loss 28

Computational evidence

Protein change
AlphaMissense	0.1282	likely benign
REVEL	0.307	indeterminate
SaProt	LLR -9.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP -3.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 48 kb · p 0.37 · regional, not allelic
Overall
CADD	29.8	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00269% African / African-American · 2/74,298 alleles

Filtering AF 0.000447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000167%

Overall 0.000632% 10/1,583,086 alleles · very rare exomes 8/1,430,996 · genomes 2/152,090 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00269%	37,149
East Asian	0.00231%	43,280
South Asian	0.00115%	86,890
European (non-Finnish)	0.000514%	194,423

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.Arg2139His
Coding: c.6416G>A
MANE Select: NM_001039141
Type: single nucleotide variant
Location: chr22:37765761 (GRCh38)
Gene constraint: LOEUF 0.865 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 40.77

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 p.Arg2139Cys Uncertain significance ★★ ⚠ same residue
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

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-arg2139his (accessed [today's date]).

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