Is THRB p.Pro452= (c.1356C>T) pathogenic?

THRB p.Pro452= (c.1356C>T) is classified Likely benign in THRB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-11). Ultra-rare (popmax 0.0481%, afr).

How common is THRB p.Pro452= (c.1356C>T) in the general population?

THRB p.Pro452= (c.1356C>T) is ultra-rare (popmax 0.0481%, afr) (gnomAD).

THRB p.Pro452=

c.1356C>T · VCV4961500

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0481%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.031	GERP -4.1, phastCons 0.28
Overall
CADD	5.795	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0481% African / African-American · 36/74,906 alleles

Filtering AF 0.0357% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0314%

Overall 0.0026% 42/1,614,070 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0481%	2,081
Admixed American	0.00667%	15,002
Remaining individualsnot grpmax-eligible	0.0016%	62,490
South Asian	0.0011%	91,084

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: THRB
Protein: p.Pro452=
Coding: c.1356C>T
MANE Select: NM_001354712
Type: single nucleotide variant
Location: chr3:24122914 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 452: the nr lbd domain; the 'interaction with nr2f6' region

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

Similar variants

THRB p.Pro452Arg Uncertain significance ★ ⚠ same residue
THRB p.Pro452Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
THRB p.Pro452Thr Uncertain significance ★ ⚠ same residue
PRSS1 p.Asn29Thr Pathogenic ★★ ⚠ same type
PRSS1 p.Lys23Arg Likely pathogenic ★★ ⚠ same type
THRB p.Ala268Gly Pathogenic/Likely pathogenic ★★ ⚠ same type
THRB p.Ala317Thr Pathogenic ★★ ⚠ same type
THRB p.Arg316His Pathogenic ★★ 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/thrb-p-pro452 (accessed [today's date]).

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