Is THRB p.Asp351= (c.1053C>T) pathogenic?

THRB p.Asp351= (c.1053C>T) is classified Likely benign in THRB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-24). Ultra-rare (popmax 0.0356%, eas); Associated with thyroid hormone resistance, generalized, autosomal dominant.

What condition is associated with THRB p.Asp351= (c.1053C>T)?

THRB p.Asp351= (c.1053C>T) is associated with thyroid hormone resistance, generalized, autosomal dominant (ClinVar).

How common is THRB p.Asp351= (c.1053C>T) in the general population?

THRB p.Asp351= (c.1053C>T) is ultra-rare (popmax 0.0356%, eas) (gnomAD).

THRB p.Asp351=

c.1053C>T · rs115445992 · VCV902711

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0356%, eas)

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 -4.1
Overall
CADD	4.049	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0356% East Asian · 16/44,882 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.0142% 229/1,614,158 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0356%	2,805
Middle Eastern	0.0165%	6,058
European (non-Finnish)	0.0164%	6,083
Remaining individualsnot grpmax-eligible	0.008%	12,501
Admixed American	0.00666%	15,005
South Asian	0.00659%	15,179
African / African-American	0.004%	25,011

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.Asp351=
Coding: c.1053C>T
MANE Select: NM_001354712
dbSNP: rs115445992
Type: single nucleotide variant
Location: chr3:24127590 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 351: 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.Asp351Asn Uncertain significance ★ ⚠ same residue
THRB p.Asp351Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-asp351 (accessed [today's date]).

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