Is TREH p.Arg215= (c.645C>T) pathogenic?

TREH p.Arg215= (c.645C>T) is classified Likely benign in TREH (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-08). Ultra-rare (popmax 0.0178%, eas); Associated with TREH-related disorder.

What condition is associated with TREH p.Arg215= (c.645C>T)?

TREH p.Arg215= (c.645C>T) is associated with TREH-related disorder (ClinVar).

How common is TREH p.Arg215= (c.645C>T) in the general population?

TREH p.Arg215= (c.645C>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

TREH p.Arg215=

c.645C>T · rs781966736 · VCV3058067

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Conditions

TREH-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.2	GERP -3.4
Overall
CADD	1.121	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0178% East Asian · 8/44,876 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00198% 32/1,613,608 alleles · ultra-rare exomes 30/1,461,458 · genomes 2/152,150 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,610
Remaining individualsnot grpmax-eligible	0.0048%	20,815
Admixed American	0.00334%	29,980
European (non-Finnish)	0.00144%	69,400
African / African-American	0.00133%	74,910
South Asian	0.0011%	91,048

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: TREH
Protein: p.Arg215=
Coding: c.645C>T
MANE Select: NM_007180
dbSNP: rs781966736
Type: single nucleotide variant
Location: chr11:118661482 (GRCh38)
Gene constraint: LOEUF 1.19 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.80

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

Disease context

TREH-related disorder

Similar variants

TREH p.Arg215Cys Uncertain significance ★ ⚠ same residue
TREH p.Arg215His Uncertain significance ★ ⚠ same residue
TREH c.423+6A>T Likely benign same condition
TREH c.424-9C>T Likely benign same condition
TREH p.Ala385= Likely benign same condition
TREH p.Arg83= Likely benign same condition
TREH p.Asp256= Likely benign same condition
TREH p.Cys354= Likely benign 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/treh-p-arg215 (accessed [today's date]).

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