Is STAT2 p.Ser605Leu (c.1814C>T) pathogenic?

STAT2 p.Ser605Leu (c.1814C>T) is classified Uncertain significance in STAT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-01). AlphaMissense: ambiguous (0.4638); Very rare (popmax 0.0011%, nfe); Associated with Inborn genetic diseases.

What condition is associated with STAT2 p.Ser605Leu (c.1814C>T)?

STAT2 p.Ser605Leu (c.1814C>T) is associated with Inborn genetic diseases (ClinVar).

How common is STAT2 p.Ser605Leu (c.1814C>T) in the general population?

STAT2 p.Ser605Leu (c.1814C>T) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about STAT2 p.Ser605Leu (c.1814C>T)?

AlphaMissense predicts ambiguous (score 0.4638) — an in-silico prediction, not a clinical call.

STAT2 p.Ser605Leu

c.1814C>T · rs1163757151 · VCV2521203

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4638 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4638	ambiguous
REVEL	0.62	indeterminate
SaProt	LLR -12.44	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.79 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 13 kb · p 6.2e-18 · regional, not allelic
Overall
CADD	26.5	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 0.0011% European (non-Finnish) · 13/1,180,040 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000867% 14/1,614,072 alleles · very rare exomes 13/1,461,894 · genomes 1/152,178 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)grpmax	0.0011%	90,772

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser605Leu
Coding: c.1814C>T
MANE Select: NM_005419
dbSNP: rs1163757151
Type: single nucleotide variant
Location: chr12:56346866 (GRCh38)
Gene constraint: LOEUF 0.497 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 6 PDB
Residue 605: the sh2 domain; a β-strand

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.Ser605= Likely benign ★★ same residue
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

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-ser605leu (accessed [today's date]).

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