Is THRB p.Asn4Ser (c.11A>G) pathogenic?

THRB p.Asn4Ser (c.11A>G) is classified Conflicting classifications of pathogenicity in THRB (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-03-13). AlphaMissense: likely benign (0.0687); Ultra-rare (popmax 0.0556%, nfe); Associated with thyroid hormone resistance, generalized, autosomal dominant.

What condition is associated with THRB p.Asn4Ser (c.11A>G)?

THRB p.Asn4Ser (c.11A>G) is associated with thyroid hormone resistance, generalized, autosomal dominant (ClinVar).

How common is THRB p.Asn4Ser (c.11A>G) in the general population?

THRB p.Asn4Ser (c.11A>G) is ultra-rare (popmax 0.0556%, nfe) (gnomAD).

What do computational predictors say about THRB p.Asn4Ser (c.11A>G)?

AlphaMissense predicts likely benign (score 0.0687) — an in-silico prediction, not a clinical call.

THRB p.Asn4Ser

c.11A>G · rs114070375 · VCV900164

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0687 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0556%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

thyroid hormone resistance, generalized, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.0687	likely benign
REVEL	0.364	indeterminate
SaProt	LLR -5.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2.5, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 76 kb · p 0.02 · regional, not allelic
Overall
CADD	22.4	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 0.0556% European (non-Finnish) · 656/1,179,362 alleles

Filtering AF 0.0521% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0506%

Overall 0.0418% 675/1,612,918 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0556%	1,798
African / African-American	0.0147%	6,817
Remaining individualsnot grpmax-eligible	0.0128%	7,807

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.Asn4Ser
Coding: c.11A>G
MANE Select: NM_001354712
dbSNP: rs114070375
Type: single nucleotide variant
Location: chr3:24228949 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 4: 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

Similar variants

PRSS1 p.Leu4= 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-asn4ser (accessed [today's date]).

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