Is THRB p.Ile59Val (c.175A>G) pathogenic?

THRB p.Ile59Val (c.175A>G) is classified Benign/Likely benign in THRB (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-10-08). AlphaMissense: likely benign (0.0678); Rare (popmax 0.395%, sas); Associated with thyroid hormone resistance, generalized, autosomal dominant.

What condition is associated with THRB p.Ile59Val (c.175A>G)?

THRB p.Ile59Val (c.175A>G) is associated with thyroid hormone resistance, generalized, autosomal dominant, selective pituitary resistance to thyroid hormone, thyroid hormone resistance, generalized, autosomal recessive (ClinVar).

How common is THRB p.Ile59Val (c.175A>G) in the general population?

THRB p.Ile59Val (c.175A>G) is rare (popmax 0.395%, sas) (gnomAD).

What do computational predictors say about THRB p.Ile59Val (c.175A>G)?

AlphaMissense predicts likely benign (score 0.0678) — an in-silico prediction, not a clinical call.

THRB p.Ile59Val

c.175A>G · rs141172732 · VCV723156

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0678 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.395%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thyroid hormone resistance, generalized, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.0678	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -5.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.71	GERP 0.044, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 76 kb · p 0.02 · regional, not allelic
Overall
CADD	16.22	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

Grpmax group 0.395% South Asian · 359/90,988 alleles

Filtering AF 0.361% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.348%

Overall 0.025% 403/1,609,754 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.395%	253
Middle Eastern	0.033%	3,027
Remaining individualsnot grpmax-eligible	0.0209%	4,796
European (non-Finnish)	0.00238%	41,999
African / African-American	0.00133%	74,984

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.Ile59Val
Coding: c.175A>G
MANE Select: NM_001354712
dbSNP: rs141172732
Type: single nucleotide variant
Location: chr3:24190182 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 59: the 'modulating' region

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

Also linked: selective pituitary resistance to thyroid hormone thyroid hormone resistance, generalized, autosomal recessive

Similar variants

PRSS1 p.Val59= Likely benign ★★ 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-ile59val (accessed [today's date]).

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