DIO2 p.Val75Ala
c.224T>C · VCV4660098
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.02%, nfe)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.315 | indeterminate |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 9.4 | GERP 2.1, phastCons 1 |
| Regional constraint | o/e 0.89 | unconstrained · MANE · 8,780 bp · p 0.049 · regional, not allelic |
| Overall | ||
| CADD | 22.7 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.02%
European (non-Finnish) · 223/1,117,468 alleles
Filtering AF
0.0178%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.017%
Overall
0.0158%
233/1,470,372 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.02% | 5,011 |
| Remaining individualsnot grpmax-eligible | 0.00877% | 11,407 |
| Finnishnot grpmax-eligible | 0.00702% | 14,236 |
| African / African-American | 0.00178% | 56,090 |
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.Val75Ala
- Coding
- c.224T>C
- MANE Select
- NM_013989
- Type
- single nucleotide variant
- Location
- chr14:80203287 (GRCh38)
- Gene constraint
- LOEUF 1.286 · pLI <0.01 (gnomAD)
Similar variants
- DIO2 p.Val89= Benign ★★ same type
- DIO2 p.Arg144Cys Uncertain significance ★ same type
- DIO2 p.Arg144His Uncertain significance ★ same type
- DIO2 p.Arg214Leu 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
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-val75ala (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown