Is PAX8 p.Pro372= (c.1116C>T) pathogenic?

PAX8 p.Pro372= (c.1116C>T) is classified Conflicting classifications of pathogenicity in PAX8 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-02-10). Rare (popmax 0.469%, eas); Associated with hypothyroidism, congenital, nongoitrous, 2.

What condition is associated with PAX8 p.Pro372= (c.1116C>T)?

PAX8 p.Pro372= (c.1116C>T) is associated with hypothyroidism, congenital, nongoitrous, 2 (ClinVar).

How common is PAX8 p.Pro372= (c.1116C>T) in the general population?

PAX8 p.Pro372= (c.1116C>T) is rare (popmax 0.469%, eas) (gnomAD).

PAX8 p.Pro372=

c.1116C>T · rs189229644 · VCV704396

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.469%, eas)

Conditions

hypothyroidism, congenital, nongoitrous, 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.31	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.6	GERP -3.5
Overall
CADD	7.358	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.469% East Asian · 210/44,756 alleles

Filtering AF 0.417% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.397%

Overall 0.0245% 395/1,610,500 alleles · rare exomes 343/1,458,212 · genomes 52/152,288 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.469%	213
Remaining individualsnot grpmax-eligible	0.093%	1,075
Admixed American	0.0806%	1,240
South Asian	0.041%	2,436
European (non-Finnish)	0.00331%	30,225
African / African-American	0.00267%	37,499
Finnishnot grpmax-eligible	0.00157%	63,652

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.Pro372=
Coding: c.1116C>T
MANE Select: NM_003466
dbSNP: rs189229644
Type: single nucleotide variant
Location: chr2:113227228 (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.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.Pro409Arg 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-pro372 (accessed [today's date]).

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