Is THRB p.Phe417= (c.1251T>C) pathogenic?

THRB p.Phe417= (c.1251T>C) is classified Benign/Likely benign in THRB (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-05-12). Low-frequency (popmax 3.53%, nfe); Associated with thyroid hormone resistance, generalized, autosomal dominant.

What condition is associated with THRB p.Phe417= (c.1251T>C)?

THRB p.Phe417= (c.1251T>C) is associated with thyroid hormone resistance, generalized, autosomal dominant (ClinVar).

How common is THRB p.Phe417= (c.1251T>C) in the general population?

THRB p.Phe417= (c.1251T>C) is low-frequency (popmax 3.53%, nfe) (gnomAD).

THRB p.Phe417=

c.1251T>C · rs13081063 · VCV257670

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.53%, nfe)

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 assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 0.94, phastCons 1
Overall
CADD	8.741	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.53% European (non-Finnish) · 41,668/1,180,026 alleles

Filtering AF 3.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.49%

Overall 3.2% 51,619/1,614,182 alleles · low-frequency exomes 47,885/1,461,884 · genomes 3,734/152,298 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	5.58%	18
European (non-Finnish)grpmax	3.53%	28
South Asian	3.07%	33
Remaining individualsnot grpmax-eligible	2.87%	35
Middle Eastern	2.44%	41
Admixed American	1.42%	71
Ashkenazi Jewishnot grpmax-eligible	1.19%	84
African / African-American	0.578%	173
East Asian	0.0111%	8,976

Finnish 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.Phe417=
Coding: c.1251T>C
MANE Select: NM_001354712
dbSNP: rs13081063
Type: single nucleotide variant
Location: chr3:24123019 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 417: the nr lbd domain; the 'interaction with nr2f6' region; an α-helix

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

Similar variants

THRB p.Ala268Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
THRB p.Ala317Thr Pathogenic ★★ ⚠ same condition
THRB p.Arg316His Pathogenic ★★ same condition
THRB p.Arg320Cys Pathogenic ★★ same condition
THRB p.Arg320His Pathogenic/Likely pathogenic ★★ same condition
THRB p.Arg338Trp Pathogenic ★★ same condition
THRB p.Arg383His Pathogenic/Likely pathogenic ★★ same condition
THRB p.Arg429Gln Pathogenic/Likely pathogenic ★★ 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/thrb-p-phe417 (accessed [today's date]).

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