Is PAX8 p.Pro409= (c.1227C>G) pathogenic?

PAX8 p.Pro409= (c.1227C>G) is classified Conflicting classifications of pathogenicity in PAX8 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2021-11-09). Ultra-rare (popmax 0.0792%, nfe); Associated with hypothyroidism, congenital, nongoitrous, 2.

What condition is associated with PAX8 p.Pro409= (c.1227C>G)?

PAX8 p.Pro409= (c.1227C>G) is associated with hypothyroidism, congenital, nongoitrous, 2 (ClinVar).

How common is PAX8 p.Pro409= (c.1227C>G) in the general population?

PAX8 p.Pro409= (c.1227C>G) is ultra-rare (popmax 0.0792%, nfe) (gnomAD).

PAX8 p.Pro409=

c.1227C>G · rs190681011 · VCV330885

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0792%, nfe)

Conditions

hypothyroidism, congenital, nongoitrous, 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.369	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP -2.4, phastCons 1
Overall
CADD	13.15	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0792% European (non-Finnish) · 934/1,179,948 alleles

Filtering AF 0.0749% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0732%

Overall 0.0616% 995/1,614,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0792%	1,263
Remaining individualsnot grpmax-eligible	0.072%	1,389
African / African-American	0.012%	8,338
Admixed American	0.01%	10,003
Finnishnot grpmax-eligible	0.00156%	63,958

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: PAX8
Protein: p.Pro409=
Coding: c.1227C>G
MANE Select: NM_003466
dbSNP: rs190681011
Type: single nucleotide variant
Location: chr2:113220141 (GRCh38)
Gene constraint: LOEUF 0.415 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 58.09 · 1 PDB

Full PAX8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypothyroidism, congenital, nongoitrous, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PAX8 p.Pro409Arg Uncertain significance ★★ same residue
PAX8 p.Arg133Gln Pathogenic/Likely pathogenic ★★ same condition
PAX8 c.*1765G>A Uncertain significance ★★ same condition
PAX8 c.*290G>A Uncertain significance ★★ same condition
PAX8 c.*845G>A Uncertain significance ★★ same condition
PAX8 p.Gln354Glu Uncertain significance ★★ ⚠ same condition
PAX8 p.Pro252Ala Uncertain significance ★★ ⚠ same condition
PAX8 p.Thr158Met Uncertain significance ★★ ⚠ same condition

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/pax8-p-pro409 (accessed [today's date]).

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