Is STAT5B p.Thr331= (c.993G>A) pathogenic?

STAT5B p.Thr331= (c.993G>A) is classified Benign/Likely benign in STAT5B (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-05-13). Low-frequency (popmax 4.95%, afr); Associated with growth hormone insensitivity with immune dysregulation 1, autosomal recessive.

What condition is associated with STAT5B p.Thr331= (c.993G>A)?

STAT5B p.Thr331= (c.993G>A) is associated with growth hormone insensitivity with immune dysregulation 1, autosomal recessive, growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant (ClinVar).

How common is STAT5B p.Thr331= (c.993G>A) in the general population?

STAT5B p.Thr331= (c.993G>A) is low-frequency (popmax 4.95%, afr) (gnomAD).

How is Laron syndrome with immunodeficiency inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

STAT5B p.Thr331=

c.993G>A · rs59491077 · VCV199128

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.95%, afr)

Conditions

growth hormone insensitivity with immune dysregulation 1, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -14	GERP -4.2
Overall
CADD	0.248	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.95% African / African-American · 3,696/74,694 alleles

Filtering AF 4.82% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.76%

Overall 0.259% 4,183/1,612,892 alleles · low-frequency exomes 2,075/1,461,398 · genomes 2,108/151,494 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.95%	20
Remaining individualsnot grpmax-eligible	0.336%	298
Admixed American	0.282%	354
Middle Eastern	0.0825%	1,212
East Asian	0.0112%	8,961
European (non-Finnish)	0.0078%	12,821
South Asian	0.00659%	15,171

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: STAT5B
Protein: p.Thr331=
Coding: c.993G>A
MANE Select: NM_012448
dbSNP: rs59491077
Type: single nucleotide variant
Location: chr17:42218327 (GRCh38)
Gene constraint: LOEUF 0.277 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.90 · 2 PDB

Full STAT5B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

growth hormone insensitivity with immune dysregulation 1, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant

For Laron syndrome with immunodeficiency (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

STAT5B p.Thr331Met Uncertain significance ★ ⚠ same residue
STAT5B c.1906+1G>A Likely pathogenic ★★ same condition
STAT5B p.Ala20Glu Uncertain significance ★★ ⚠ same condition
STAT5B p.Ala20Val Uncertain significance ★★ ⚠ same condition
STAT5B p.Ala213Gly Uncertain significance ★★ ⚠ same condition
STAT5B p.Ala213Ser Uncertain significance ★★ ⚠ same condition
STAT5B p.Ala723Thr Uncertain significance ★★ ⚠ same condition
STAT5B p.Ala785Thr Uncertain significance ★★ ⚠ 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/stat5b-p-thr331 (accessed [today's date]).

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