Is THRB p.Phe245= (c.735C>T) pathogenic?

THRB p.Phe245= (c.735C>T) is classified Benign in THRB (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-05-11). Common (popmax 22.1%, sas) — too common for a highly-penetrant pathogenic allele; Associated with thyroid hormone resistance, generalized, autosomal dominant.

What condition is associated with THRB p.Phe245= (c.735C>T)?

THRB p.Phe245= (c.735C>T) is associated with thyroid hormone resistance, generalized, autosomal dominant (ClinVar).

THRB p.Phe245=

Q: How common is THRB p.Phe245= (c.735C>T) in the general population?

THRB p.Phe245= (c.735C>T) is common (popmax 22.1%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.735C>T · rs3752874 · VCV198422

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 22.1%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

thyroid hormone resistance, generalized, autosomal dominant

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.8	GERP -1.5, phastCons 1
Overall
CADD	9.624	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 22.1% South Asian · 20,146/91,070 alleles

Filtering AF 21.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.8%

Overall 15.4% 249,137/1,613,814 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	22.8%	4
South Asiangrpmax	22.1%	5
Middle Eastern	20.2%	5
Admixed American	17.1%	6
Remaining individualsnot grpmax-eligible	16.1%	6
European (non-Finnish)	15.2%	7
African / African-American	14.3%	7
Finnishnot grpmax-eligible	12.5%	8
Amishnot grpmax-eligible	11.5%	9
East Asian	5.52%	18

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe245=
Coding: c.735C>T
dbSNP: rs3752874
Type: single nucleotide variant
Location: chr3:24143504 (GRCh38)

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

Disease context

thyroid hormone resistance, generalized, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-phe245 (accessed [today's date]).

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