Is RNASEH2B p.Pro43= (c.129C>A) pathogenic?

RNASEH2B p.Pro43= (c.129C>A) is classified Likely benign in RNASEH2B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-05). Ultra-rare (popmax 0.0112%, eas); Associated with Aicardi-Goutieres syndrome 2.

What condition is associated with RNASEH2B p.Pro43= (c.129C>A)?

RNASEH2B p.Pro43= (c.129C>A) is associated with Aicardi-Goutieres syndrome 2 (ClinVar).

How common is RNASEH2B p.Pro43= (c.129C>A) in the general population?

RNASEH2B p.Pro43= (c.129C>A) is ultra-rare (popmax 0.0112%, eas) (gnomAD).

How is Aicardi-Goutières syndrome inherited?

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

RNASEH2B p.Pro43=

c.129C>A · rs199839728 · VCV1543958

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, eas)

Conditions

Aicardi-Goutieres syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.4	GERP -7.9
Overall
CADD	0.272	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0112% East Asian · 5/44,648 alleles

Filtering AF 0.00436% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00277%

Overall 0.000314% 5/1,593,322 alleles · ultra-rare exomes 3/1,441,046 · genomes 2/152,276 · 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: RNASEH2B
Protein: p.Pro43=
Coding: c.129C>A
MANE Select: NM_024570
dbSNP: rs199839728
Type: single nucleotide variant
Location: chr13:50927471 (GRCh38)
Gene constraint: LOEUF 1.401 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.22 · 4 PDB
Residue 43: a turn; a UniProt-annotated variant site (in ags2)

Full RNASEH2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Aicardi-Goutieres syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Aicardi-Goutières syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Antenatal, Infancy, Neonatal
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

RNASEH2B p.Pro43His Uncertain significance ★★ ⚠ same residue
RNASEH2B p.Pro43Ser Uncertain significance ★★ ⚠ same residue
RNASEH2B c.322-2A>T Likely pathogenic ★★ same condition
RNASEH2B c.322-3C>G Likely pathogenic ★★ same condition
RNASEH2B c.437-1G>A Pathogenic/Likely pathogenic ★★ same condition
RNASEH2B c.510+1G>A Pathogenic ★★ same condition
RNASEH2B c.511-1G>A Pathogenic/Likely pathogenic ★★ same condition
RNASEH2B c.65-13G>A Pathogenic/Likely pathogenic ★★ 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/rnaseh2b-p-pro43 (accessed [today's date]).

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