Is THRA p.Ser45Ile (c.134G>T) pathogenic?

THRA p.Ser45Ile (c.134G>T) is classified Pathogenic in THRA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2015-05-01). AlphaMissense: likely pathogenic (0.9824); Absent from gnomAD v4.1; Associated with congenital nongoitrous hypothyroidism 6.

What condition is associated with THRA p.Ser45Ile (c.134G>T)?

THRA p.Ser45Ile (c.134G>T) is associated with congenital nongoitrous hypothyroidism 6 (ClinVar).

How common is THRA p.Ser45Ile (c.134G>T) in the general population?

THRA p.Ser45Ile (c.134G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about THRA p.Ser45Ile (c.134G>T)?

AlphaMissense predicts likely pathogenic (score 0.9824) — an in-silico prediction, not a clinical call.

THRA p.Ser45Ile

c.134G>T · rs137853162 · VCV29913

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9824 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital nongoitrous hypothyroidism 6

Computational evidence

Protein change
AlphaMissense	0.9824	likely pathogenic ✓ concordant with ClinVar
REVEL	0.755	pathogenic-leaning
SaProt	LLR -12.47	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 6,939 bp · p 2.2e-08 · 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: THRA
Protein: p.Ser45Ile
Coding: c.134G>T
MANE Select: NM_199334
dbSNP: rs137853162
Type: single nucleotide variant
Location: chr17:40077520 (GRCh38)
Gene constraint: LOEUF 0.439 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 74.23 · 10 PDB
Residue 45: the 'modulating' region

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

Disease context

congenital nongoitrous hypothyroidism 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

THRA p.Ala263Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
THRA p.Glu403Lys Pathogenic/Likely pathogenic ★★ same condition
THRA p.Gly291Ser Pathogenic/Likely pathogenic ★★ same condition
THRA p.Glu173Gly Likely pathogenic ★ same condition
THRA p.His381Tyr Likely pathogenic ★ same condition
THRA p.Ile299Thr Likely pathogenic ★ ⚠ same condition
THRA p.Thr273Asn Likely pathogenic ★ same condition
THRA c.121+1G>A Uncertain significance ★ 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/thra-p-ser45ile (accessed [today's date]).

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