GPHA2

Chr 11

glycoprotein hormone subunit alpha 2

Also known as: A2, GPA2, ZSIG51

NCBI Gene: 170589 ENSG00000149735 UniProt: Q96T91 OMIM: 609651

The GPHA2 protein forms a heterodimeric glycoprotein hormone with GPHB5 that binds and activates the thyroid-stimulating hormone receptor, controlling thyroid cell metabolism through increased cAMP production. Mutations cause isolated central hypothyroidism with autosomal recessive inheritance. The gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

GPHA2 is a cystine knot-forming polypeptide and a subunit of the dimeric glycoprotein hormone family (Hsu et al., 2002 [PubMed 12089349]).[supplied by OMIM, Mar 2008]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.94

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.94LOEUF

pLI 0.000

Z-score -1.27

OE 1.54 (0.90–1.94)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.09Z-score

OE missense 0.97 (0.81–1.18)

75 obs / 77.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.54 (0.90–1.94)

0≤0.351.4

Missense OE?0.97 (0.81–1.18)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 10 / 6.5Missense obs/exp: 75 / 77.2Syn Z: 0.61

Background carrier burden — how many people carry a rare variant somewhere in GPHA2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 220

194 rare PASS variants

Rare truncating (LoF)

1 in 820

46 rare PASS variants

Rare synonymous (reference)

1 in 230

71 rare PASS variants

Rare missense and truncating variants are carried at similar rates in GPHA2; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 220	1 in 950
South Asian	~43k	1 in 260	1 in 2,400
Remaining (unassigned)	~30k	1 in 180	1 in 840
European (Finnish)	~27k	1 in 5,300	1 in 5,300
Admixed American	~22k	1 in 190	1 in 860
African / African American	~21k	1 in 260	1 in 770
East Asian	~20k	1 in 240	1 in 950
Ashkenazi Jewish	~13k	≈ 1 in 3,300	none seen
Middle Eastern	~2,884	1 in 220	≈ 1 in 2,800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓