Is DIO3 p.Gln233His (c.699G>T) pathogenic?

DIO3 p.Gln233His (c.699G>T) is classified Uncertain significance in DIO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-18). Very rare (popmax 0.00878%, sas).

How common is DIO3 p.Gln233His (c.699G>T) in the general population?

DIO3 p.Gln233His (c.699G>T) is very rare (popmax 0.00878%, sas) (gnomAD).

DIO3 p.Gln233His

c.699G>T · rs760000345 · VCV2548414

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.013	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 0.75, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 397 bp · p 2.1e-05 · regional, not allelic
Overall
CADD	19.55	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00878% South Asian · 8/91,082 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.000548% 8/1,459,980 alleles · very 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: DIO3
Protein: p.Gln233His
Coding: c.699G>T
MANE Select: NM_001362
dbSNP: rs760000345
Type: single nucleotide variant
Location: chr14:101562195 (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.Arg75Cys 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-gln233his (accessed [today's date]).

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