Is PAX8 p.Pro409Arg (c.1226C>G) pathogenic?

PAX8 p.Pro409Arg (c.1226C>G) is classified Uncertain significance in PAX8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-10). AlphaMissense: ambiguous (0.4507); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with PAX8 p.Pro409Arg (c.1226C>G)?

PAX8 p.Pro409Arg (c.1226C>G) is associated with Inborn genetic diseases, hypothyroidism, congenital, nongoitrous, 2 (ClinVar).

How common is PAX8 p.Pro409Arg (c.1226C>G) in the general population?

PAX8 p.Pro409Arg (c.1226C>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about PAX8 p.Pro409Arg (c.1226C>G)?

AlphaMissense predicts ambiguous (score 0.4507) — an in-silico prediction, not a clinical call.

PAX8 p.Pro409Arg

c.1226C>G · rs369313070 · VCV870687

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4507 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4507	ambiguous
REVEL	0.39	indeterminate
SaProt	LLR -8.02	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP -2.4, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 24 kb · p 0.083 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,016 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00161% 26/1,614,016 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,008
East Asian	0.00223%	44,872
European (non-Finnish)	0.00186%	53,635
Remaining individualsnot grpmax-eligible	0.0016%	62,506

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.Pro409Arg
Coding: c.1226C>G
MANE Select: NM_003466
dbSNP: rs369313070
Type: single nucleotide variant
Location: chr2:113220142 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypothyroidism, congenital, nongoitrous, 2

Similar variants

PAX8 p.Pro409= Conflicting classifications of pathogenicity ★ 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.Gly11Arg Uncertain significance ★★ ⚠ same condition
PAX8 p.Leu266Ser 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-pro409arg (accessed [today's date]).

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