Is STAT2 p.Pro709Leu (c.2126C>T) pathogenic?

STAT2 p.Pro709Leu (c.2126C>T) is classified Uncertain significance in STAT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely benign (0.0805); Very rare (popmax 0.00232%, sas).

How common is STAT2 p.Pro709Leu (c.2126C>T) in the general population?

STAT2 p.Pro709Leu (c.2126C>T) is very rare (popmax 0.00232%, sas) (gnomAD).

What do computational predictors say about STAT2 p.Pro709Leu (c.2126C>T)?

AlphaMissense predicts likely benign (score 0.0805) — an in-silico prediction, not a clinical call.

STAT2 p.Pro709Leu

c.2126C>T · VCV3764304

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0805 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00232%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0805	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -6.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -0.51, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 13 kb · p 6.2e-18 · regional, not allelic
Overall
CADD	11.31	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00232% South Asian · 2/86,060 alleles

Filtering AF 0.000823% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000666%

Overall 0.00128% 20/1,560,776 alleles · very rare exomes 14/1,408,584 · genomes 6/152,192 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00232%	43,030
Remaining individualsnot grpmax-eligible	0.00165%	60,456
European (non-Finnish)	0.00139%	71,948
African / African-American	0.00136%	73,370

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: STAT2
Protein: p.Pro709Leu
Coding: c.2126C>T
MANE Select: NM_005419
Type: single nucleotide variant
Location: chr12:56344112 (GRCh38)
Gene constraint: LOEUF 0.497 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 6 PDB

Full STAT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

STAT2 p.Pro709= Likely benign ★★ same residue
STAT2 p.Arg667Ter Pathogenic/Likely pathogenic ★★ same type
STAT2 p.Gln274Ter Pathogenic/Likely pathogenic ★★ same type
STAT2 p.Ala219Thr Uncertain significance ★★ ⚠ same type
STAT2 p.Ala302Thr Uncertain significance ★★ ⚠ same type
STAT2 p.Arg300Cys Uncertain significance ★★ ⚠ same type
STAT2 p.Arg330Gln Uncertain significance ★★ ⚠ same type
STAT2 p.Arg409His Uncertain significance ★★ ⚠ 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/stat2-p-pro709leu (accessed [today's date]).

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