Is DIO3 p.Arg75Cys (c.223C>T) pathogenic?

DIO3 p.Arg75Cys (c.223C>T) is classified Uncertain significance in DIO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-17). Absent from gnomAD v4.1.

How common is DIO3 p.Arg75Cys (c.223C>T) in the general population?

DIO3 p.Arg75Cys (c.223C>T) is absent from gnomAD v4.1 (gnomAD).

DIO3 p.Arg75Cys

c.223C>T · rs1178675572 · VCV2308491

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.062	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.75	GERP -2.4, phastCons 0.83
Regional constraint	o/e 0.90	unconstrained · MANE · 473 bp · p 0.13 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DIO3
Protein: p.Arg75Cys
Coding: c.223C>T
MANE Select: NM_001362
dbSNP: rs1178675572
Type: single nucleotide variant
Location: chr14:101561719 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI 0.95 (gnomAD)

Full DIO3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DIO3 p.Ala155Val Uncertain significance ★ same type
DIO3 p.Ala20Thr Uncertain significance ★ same type
DIO3 p.Ala240Thr Uncertain significance ★ same type
DIO3 p.Ala40Gly Uncertain significance ★ same type
DIO3 p.Ala40Val Uncertain significance ★ same type
DIO3 p.Arg291Ser Uncertain significance ★ same type
DIO3 p.Arg300Trp Uncertain significance ★ same type
DIO3 p.Asn164Ser 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/dio3-p-arg75cys (accessed [today's date]).

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