Is DIO1 p.Ile224Val (c.670A>G) pathogenic?

DIO1 p.Ile224Val (c.670A>G) is classified Uncertain significance in DIO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). Very rare (popmax 0.00432%, nfe).

How common is DIO1 p.Ile224Val (c.670A>G) in the general population?

DIO1 p.Ile224Val (c.670A>G) is very rare (popmax 0.00432%, nfe) (gnomAD).

DIO1 p.Ile224Val

c.670A>G · rs772813708 · VCV2205484

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00432%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.052	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 2.2, phastCons 1
Overall
CADD	15.29	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00432% European (non-Finnish) · 51/1,179,310 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00341% 55/1,612,354 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00481%	20,799
European (non-Finnish)grpmax	0.00432%	23,124
African / African-American	0.00133%	74,908

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: DIO1
Protein: p.Ile224Val
Coding: c.670A>G
MANE Select: NM_001193369 · reported on NM_000792
dbSNP: rs772813708
Type: single nucleotide variant
Location: chr1:53906283 (GRCh38)
Structure: AlphaFold pLDDT 46.89 · 2 PDB
Residue 224: the 'disordered' region

Full DIO1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DIDO1 p.Asp1443= Benign ★★ same type
DIDO1 p.Glu1498Ala Likely benign ★★ same type
DIDO1 p.Glu1630Lys Benign ★★ same type
DIDO1 p.Leu1706Val Benign ★★ same type
DIDO1 p.Pro136= Benign ★★ same type
DIDO1 p.Pro616Leu Likely benign ★★ same type
DIDO1 p.Ser537= Benign ★★ same type
DIDO1 p.Ser877= Benign ★★ 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/dio1-p-ile224val (accessed [today's date]).

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