Is THRB p.Val458Ala (c.1373T>C) pathogenic?

THRB p.Val458Ala (c.1373T>C) is classified Likely pathogenic in THRB (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-12-30). AlphaMissense: likely pathogenic (0.9891); Absent from gnomAD v4.1; Associated with THRB-related disorder.

What condition is associated with THRB p.Val458Ala (c.1373T>C)?

THRB p.Val458Ala (c.1373T>C) is associated with THRB-related disorder, thyroid hormone resistance, generalized, autosomal dominant (ClinVar).

How common is THRB p.Val458Ala (c.1373T>C) in the general population?

THRB p.Val458Ala (c.1373T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about THRB p.Val458Ala (c.1373T>C)?

AlphaMissense predicts likely pathogenic (score 0.9891) — an in-silico prediction, not a clinical call.

THRB p.Val458Ala

c.1373T>C · rs121918704 · VCV12564

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9891 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

THRB-related disorder

Computational evidence

Protein change
AlphaMissense	0.9891	likely pathogenic ✓ concordant with ClinVar
REVEL	0.888	moderately pathogenic-leaning
SaProt	LLR -10.59	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.15	constrained · MANE · 103 bp · p 5.9e-09 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: THRB
Protein: p.Val458Ala
Coding: c.1373T>C
MANE Select: NM_001354712
dbSNP: rs121918704
Type: single nucleotide variant
Location: chr3:24122897 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 458: the nr lbd domain; an α-helix; the 'interaction with nr2f6' region

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

Disease context

THRB-related disorder

Also linked: thyroid hormone resistance, generalized, autosomal dominant

Similar variants

THRB p.Val458Gly Uncertain significance ★ ⚠ 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
THRB p.Arg383His 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-val458ala (accessed [today's date]).

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