Is DIO3 p.Ser148Arg (c.444C>G) pathogenic?

DIO3 p.Ser148Arg (c.444C>G) is classified Uncertain significance in DIO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-17). Very rare (popmax 0.00297%, nfe).

How common is DIO3 p.Ser148Arg (c.444C>G) in the general population?

DIO3 p.Ser148Arg (c.444C>G) is very rare (popmax 0.00297%, nfe) (gnomAD).

DIO3 p.Ser148Arg

c.444C>G · rs376254414 · VCV2462827

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00297%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.058	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.15	GERP -3.1, phastCons 0.92
Regional constraint	o/e 0.90	unconstrained · MANE · 473 bp · p 0.13 · regional, not allelic
Overall
CADD	12.49	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00297% European (non-Finnish) · 35/1,179,968 alleles

Filtering AF 0.00215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.00237% 38/1,603,856 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00297%	33,713
African / African-American	0.00267%	37,476
East Asian	0.00223%	44,890

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.Ser148Arg
Coding: c.444C>G
MANE Select: NM_001362
dbSNP: rs376254414
Type: single nucleotide variant
Location: chr14:101561940 (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-ser148arg (accessed [today's date]).

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