Is DIO2 p.Arg214Leu (c.641G>T) pathogenic?

DIO2 p.Arg214Leu (c.641G>T) is classified Uncertain significance in DIO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-15). Ultra-rare (popmax 0.0111%, eas).

How common is DIO2 p.Arg214Leu (c.641G>T) in the general population?

DIO2 p.Arg214Leu (c.641G>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

DIO2 p.Arg214Leu

c.641G>T · VCV3272084

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.103	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 8,780 bp · p 0.049 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,860 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000342% 5/1,461,708 alleles · ultra-rare

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: DIO2
Protein: p.Arg214Leu
Coding: c.641G>T
MANE Select: NM_013989
Type: single nucleotide variant
Location: chr14:80202870 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)

Full DIO2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DIO2 p.Val89= Benign ★★ same type
DIO2 p.Arg144Cys Uncertain significance ★ same type
DIO2 p.Arg144His Uncertain significance ★ same type
DIO2 p.Arg255Trp Uncertain significance ★ same type
DIO2 p.Arg61His Uncertain significance ★ same type
DIO2 p.Asn100Ser Uncertain significance ★ same type
DIO2 p.Gln207Glu Uncertain significance ★ same type
DIO2 p.Glu149Ala Uncertain significance ★ same type

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/dio2-p-arg214leu (accessed [today's date]).

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