Is THRB p.Arg338Gln (c.1013G>A) pathogenic?

THRB p.Arg338Gln (c.1013G>A) is classified Uncertain significance in THRB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-06). AlphaMissense: likely pathogenic (0.6489); Very rare (popmax 0.00134%, afr).

How common is THRB p.Arg338Gln (c.1013G>A) in the general population?

THRB p.Arg338Gln (c.1013G>A) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about THRB p.Arg338Gln (c.1013G>A)?

AlphaMissense predicts likely pathogenic (score 0.6489) — an in-silico prediction, not a clinical call.

THRB p.Arg338Gln

c.1013G>A · rs1276992783 · VCV2573413

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6489 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6489	likely pathogenic
REVEL	0.77	pathogenic-leaning
SaProt	LLR -12.93	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

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,894 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,614,012 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,894
European (non-Finnish)	0.000508%	196,671

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.Arg338Gln
Coding: c.1013G>A
MANE Select: NM_001354712
dbSNP: rs1276992783
Type: single nucleotide variant
Location: chr3:24127630 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 338: the nr lbd domain; a UniProt-annotated variant site (in grthd); the 'interaction with nr2f6' region; an α-helix

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

Similar variants

THRB p.Arg338Trp Pathogenic ★★ same residue
PRSS1 p.Asn29Thr Pathogenic ★★ ⚠ same type
PRSS1 p.Lys23Arg Likely pathogenic ★★ ⚠ same type
THRB p.Ala268Gly Pathogenic/Likely pathogenic ★★ same type
THRB p.Ala317Thr Pathogenic ★★ same type
THRB p.Arg316His Pathogenic ★★ same type
THRB p.Arg320Cys Pathogenic ★★ same type
THRB p.Arg320His Pathogenic/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-arg338gln (accessed [today's date]).

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