Is TRIOBP p.Ala2012Val (c.6035C>T) pathogenic?

TRIOBP p.Ala2012Val (c.6035C>T) is classified Uncertain significance in TRIOBP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-09). AlphaMissense: likely benign (0.1727); Ultra-rare (popmax 0.0133%, amr); Associated with Inborn genetic diseases.

What condition is associated with TRIOBP p.Ala2012Val (c.6035C>T)?

TRIOBP p.Ala2012Val (c.6035C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TRIOBP p.Ala2012Val (c.6035C>T) in the general population?

TRIOBP p.Ala2012Val (c.6035C>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about TRIOBP p.Ala2012Val (c.6035C>T)?

AlphaMissense predicts likely benign (score 0.1727) — an in-silico prediction, not a clinical call.

TRIOBP p.Ala2012Val

c.6035C>T · VCV3342406

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1727 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1727	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -7.25	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 2.3	GERP 2.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 48 kb · p 0.37 · regional, not allelic
Overall
CADD	24.4	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 0.0133% Admixed American · 7/52,758 alleles

Filtering AF 0.0062% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00433%

Overall 0.00229% 36/1,569,488 alleles · ultra-rare exomes 33/1,417,370 · genomes 3/152,118 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,537
European (non-Finnish)	0.00242%	41,363
Remaining individualsnot grpmax-eligible	0.00164%	60,900

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.Ala2012Val
Coding: c.6035C>T
MANE Select: NM_001039141
Type: single nucleotide variant
Location: chr22:37757960 (GRCh38)
Gene constraint: LOEUF 0.865 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 40.77
Residue 2012: the 'disordered' region

Full TRIOBP 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

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TRIOBP p.Ala414Val Uncertain significance ★★ ⚠ same condition
TRIOBP p.Arg1368Trp Uncertain significance ★★ ⚠ same condition
TRIOBP p.Arg1930Trp Uncertain significance ★★ ⚠ same condition
TRIOBP p.Arg1960Cys Uncertain significance ★★ ⚠ same condition
TRIOBP p.Arg1964Cys Uncertain significance ★★ ⚠ same condition
TRIOBP p.Arg1964His 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/triobp-p-ala2012val (accessed [today's date]).

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