Is THRB p.Met1Val (c.1A>G) pathogenic?

THRB p.Met1Val (c.1A>G) is classified Uncertain significance in THRB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-10-11). Ultra-rare (popmax 0.033%, mid).

How common is THRB p.Met1Val (c.1A>G) in the general population?

THRB p.Met1Val (c.1A>G) is ultra-rare (popmax 0.033%, mid) (gnomAD).

THRB p.Met1Val

c.1A>G · rs886044192 · VCV289505

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function in a LoF-intolerant gene
REVEL	0.629	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2.5, phastCons 1
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,052 alleles

Filtering AF 0.00583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000372% 6/1,612,092 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,026
Admixed American	0.00167%	59,936
South Asian	0.0011%	90,854
European (non-Finnish)	0.00017%	589,487

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.Met1Val
Coding: c.1A>G
MANE Select: NM_001354712
dbSNP: rs886044192
Type: single nucleotide variant
Location: chr3:24228959 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.24 · 34 PDB
Residue 1: the 'modulating' region

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

Similar variants

PRSS1 p.Met1Leu Uncertain significance ★★ 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-met1val (accessed [today's date]).

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