Is CGAS p.Arg457Cys (c.1369C>T) pathogenic?

CGAS p.Arg457Cys (c.1369C>T) is classified Uncertain significance in CGAS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-09). AlphaMissense: likely benign (0.1171); Very rare (popmax 0.00439%, sas).

How common is CGAS p.Arg457Cys (c.1369C>T) in the general population?

CGAS p.Arg457Cys (c.1369C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about CGAS p.Arg457Cys (c.1369C>T)?

AlphaMissense predicts likely benign (score 0.1171) — an in-silico prediction, not a clinical call.

CGAS p.Arg457Cys

c.1369C>T · rs1031745357 · VCV3143852

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1171 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1171	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -8.19	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 -1.6	GERP -4.3
Regional constraint	o/e 0.84	unconstrained · MANE · 20 kb · p 0.0032 · regional, not allelic
Overall
CADD	3.045	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 0.00439% South Asian · 4/91,064 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000805% 13/1,613,926 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,766
African / African-American	0.00267%	37,442
Admixed American	0.00167%	59,950
European (non-Finnish)	0.000508%	196,671

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: CGAS
Protein: p.Arg457Cys
Coding: c.1369C>T
MANE Select: NM_138441
dbSNP: rs1031745357
Type: single nucleotide variant
Location: chr6:73425427 (GRCh38)
Gene constraint: LOEUF 1.529 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.38 · 107 PDB
Residue 457: an α-helix

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

Similar variants

CGAS p.Arg457His Uncertain significance ★ ⚠ same residue
CGAS p.Ala109Glu Uncertain significance ★ ⚠ same type
CGAS p.Ala118Asp Uncertain significance ★ ⚠ same type
CGAS p.Ala158Val Uncertain significance ★ ⚠ same type
CGAS p.Ala167Pro Uncertain significance ★ ⚠ same type
CGAS p.Ala167Val Uncertain significance ★ ⚠ same type
CGAS p.Ala17Gly Conflicting classifications of pathogenicity ★ ⚠ same type
CGAS p.Ala247Glu 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/cgas-p-arg457cys (accessed [today's date]).

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