Is RNASEH2A p.Arg235Pro (c.704G>C) pathogenic?

RNASEH2A p.Arg235Pro (c.704G>C) is classified Likely pathogenic in RNASEH2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-04). AlphaMissense: likely pathogenic (0.9829); Absent from gnomAD v4.1; Associated with Aicardi-Goutieres syndrome 4.

What condition is associated with RNASEH2A p.Arg235Pro (c.704G>C)?

RNASEH2A p.Arg235Pro (c.704G>C) is associated with Aicardi-Goutieres syndrome 4 (ClinVar).

How common is RNASEH2A p.Arg235Pro (c.704G>C) in the general population?

RNASEH2A p.Arg235Pro (c.704G>C) is absent from gnomAD v4.1 (gnomAD).

How is Aicardi-Goutières syndrome inherited?

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

What do computational predictors say about RNASEH2A p.Arg235Pro (c.704G>C)?

AlphaMissense predicts likely pathogenic (score 0.9829) — an in-silico prediction, not a clinical call.

RNASEH2A p.Arg235Pro

c.704G>C · rs75718910 · VCV3067855

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9829 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Aicardi-Goutieres syndrome 4

Computational evidence

Protein change
AlphaMissense	0.9829	likely pathogenic ✓ concordant with ClinVar · top 4% in RNASEH2A
REVEL	0.98	strongly pathogenic-leaning
SaProt	LLR -15.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 6,789 bp · p 0.59 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RNASEH2A
Protein: p.Arg235Pro
Coding: c.704G>C
MANE Select: NM_006397
dbSNP: rs75718910
Type: single nucleotide variant
Location: chr19:12813149 (GRCh38)
Gene constraint: LOEUF 1.164 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.69 · 3 PDB
Residue 235: the rnase h type-2 domain; a UniProt-annotated variant site (in ags4)

Full RNASEH2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Aicardi-Goutieres syndrome 4 — 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

RNASEH2A p.Arg235Gln Likely pathogenic ★★ same residue
RNASEH2A p.Arg235Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
RNASEH2A p.Arg235= Likely benign ★ same residue
RNASEH2A c.199+1G>C Likely pathogenic ★★ same condition
RNASEH2A p.Arg186Gln Pathogenic/Likely pathogenic ★★ same condition
RNASEH2A p.Arg186Trp Pathogenic/Likely pathogenic ★★ same condition
RNASEH2A p.Trp219Ter Pathogenic/Likely pathogenic ★★ same condition
RNASEH2A c.411+3G>C 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/rnaseh2a-p-arg235pro (accessed [today's date]).

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