Is STAT2 p.Leu500Phe (c.1498C>T) pathogenic?

STAT2 p.Leu500Phe (c.1498C>T) is classified Uncertain significance in STAT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: ambiguous (0.4512); Very rare (popmax 0.00445%, eas); Associated with Inborn genetic diseases.

What condition is associated with STAT2 p.Leu500Phe (c.1498C>T)?

STAT2 p.Leu500Phe (c.1498C>T) is associated with Inborn genetic diseases (ClinVar).

How common is STAT2 p.Leu500Phe (c.1498C>T) in the general population?

STAT2 p.Leu500Phe (c.1498C>T) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about STAT2 p.Leu500Phe (c.1498C>T)?

AlphaMissense predicts ambiguous (score 0.4512) — an in-silico prediction, not a clinical call.

STAT2 p.Leu500Phe

c.1498C>T · VCV3963106

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4512 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4512	ambiguous
REVEL	0.896	moderately pathogenic-leaning
SaProt	LLR -12.07	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 13 kb · p 6.2e-18 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,896 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000124% 2/1,613,870 alleles · very rare exomes 0/1,461,686 · genomes 2/152,184 · joint denominator

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.Leu500Phe
Coding: c.1498C>T
MANE Select: NM_005419
Type: single nucleotide variant
Location: chr12:56349002 (GRCh38)
Gene constraint: LOEUF 0.497 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 6 PDB
Residue 500: the 'mediates interaction with usp18' region; the 'interaction with heartland virus nss' region; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

STAT2 p.Ala219Thr Uncertain significance ★★ ⚠ same condition
STAT2 p.Ala302Thr Uncertain significance ★★ ⚠ same condition
STAT2 p.Arg300Cys Uncertain significance ★★ ⚠ same condition
STAT2 p.Arg409His Uncertain significance ★★ ⚠ same condition
STAT2 p.Arg576Cys Uncertain significance ★★ ⚠ same condition
STAT2 p.Arg646Cys Uncertain significance ★★ ⚠ same condition
STAT2 p.Asn700Ser Uncertain significance ★★ ⚠ same condition
STAT2 p.Asp558Glu 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/stat2-p-leu500phe (accessed [today's date]).

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