Is DIO3 p.Pro94Ala (c.280C>G) pathogenic?

DIO3 p.Pro94Ala (c.280C>G) is classified Uncertain significance in DIO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-13). Ultra-rare (popmax 0.043%, nfe).

How common is DIO3 p.Pro94Ala (c.280C>G) in the general population?

DIO3 p.Pro94Ala (c.280C>G) is ultra-rare (popmax 0.043%, nfe) (gnomAD).

DIO3 p.Pro94Ala

c.280C>G · rs368850596 · VCV2265785

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.043%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.027	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 473 bp · p 0.13 · regional, not allelic
Overall
CADD	17.38	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.043% European (non-Finnish) · 507/1,179,958 alleles

Filtering AF 0.0398% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0386%

Overall 0.0323% 520/1,611,966 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.043%	2,327
Remaining individualsnot grpmax-eligible	0.0144%	6,940
African / African-American	0.00534%	18,735

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.Pro94Ala
Coding: c.280C>G
MANE Select: NM_001362
dbSNP: rs368850596
Type: single nucleotide variant
Location: chr14:101561776 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI 0.95 (gnomAD)
Residue 94: the 'disordered' region

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-pro94ala (accessed [today's date]).

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