Is THRB p.Arg316His (c.947G>A) pathogenic?

THRB p.Arg316His (c.947G>A) is classified Pathogenic in THRB (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-07-08). AlphaMissense: likely pathogenic (0.9685); Very rare (popmax 0.00223%, eas); Associated with THRB-related disorder.

How common is THRB p.Arg316His (c.947G>A) in the general population?

THRB p.Arg316His (c.947G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about THRB p.Arg316His (c.947G>A)?

AlphaMissense predicts likely pathogenic (score 0.9685) — an in-silico prediction, not a clinical call.

THRB p.Arg316His

Q: What condition is associated with THRB p.Arg316His (c.947G>A)?

THRB p.Arg316His (c.947G>A) is associated with THRB-related disorder, selective pituitary resistance to thyroid hormone, thyroid hormone resistance, generalized, autosomal dominant (ClinVar).

c.947G>A · rs121918695 · VCV12555

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9685 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

THRB-related disorder

Computational evidence

Protein change
AlphaMissense	0.9685	likely pathogenic ✓ concordant with ClinVar
REVEL	0.929	moderately pathogenic-leaning
SaProt	LLR -14.12	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 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 10 kb · p 5.8e-19 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.00223% East Asian · 1/44,882 alleles

Overall 6.84e-05% 1/1,461,878 alleles · very rare

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.Arg316His
Coding: c.947G>A
MANE Select: NM_001354712
dbSNP: rs121918695
Type: single nucleotide variant
Location: chr3:24127696 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 316: the nr lbd domain; a UniProt-annotated variant site (in prth; impairs hormone binding); the 'interaction with nr2f6' region; an α-helix

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

Disease context

THRB-related disorder

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

Similar variants

THRB p.Ala268Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
THRB p.Ala317Thr 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
THRB p.Arg429Gln Pathogenic/Likely pathogenic ★★ same condition
THRB p.Arg438Cys 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-arg316his (accessed [today's date]).

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