Is THRB p.Val349Glu (c.1046T>A) pathogenic?

THRB p.Val349Glu (c.1046T>A) is classified Likely pathogenic in THRB (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-04-05). AlphaMissense: likely pathogenic (0.9963); Absent from gnomAD v4.1; Associated with thyroid hormone resistance syndrome.

What condition is associated with THRB p.Val349Glu (c.1046T>A)?

THRB p.Val349Glu (c.1046T>A) is associated with thyroid hormone resistance syndrome (ClinVar).

How common is THRB p.Val349Glu (c.1046T>A) in the general population?

THRB p.Val349Glu (c.1046T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about THRB p.Val349Glu (c.1046T>A)?

AlphaMissense predicts likely pathogenic (score 0.9963) — an in-silico prediction, not a clinical call.

THRB p.Val349Glu

c.1046T>A · VCV4856669

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9963 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thyroid hormone resistance syndrome

Computational evidence

Protein change
AlphaMissense	0.9963	likely pathogenic ✓ concordant with ClinVar
REVEL	0.962	strongly pathogenic-leaning
SaProt	LLR -14.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 10 kb · p 5.8e-19 · regional, not allelic
Overall
CADD	32.0	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.Val349Glu
Coding: c.1046T>A
MANE Select: NM_001354712
Type: single nucleotide variant
Location: chr3:24127597 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 349: 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 syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

THRB p.Val349Met Likely pathogenic ★★ ⚠ same residue
THRB p.Val349= Likely benign same residue
THRB p.Ala268Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
THRB p.Ala317Thr Pathogenic ★★ ⚠ same condition
THRB p.Gly332Glu Likely pathogenic ★★ same condition
THRB p.His435Gln Pathogenic ★★ ⚠ same condition
PRSS1 p.Asn29Thr Pathogenic ★★ ⚠ same type
PRSS1 p.Lys23Arg Likely 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-val349glu (accessed [today's date]).

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