Is RNASEH2A p.Pro44= (c.132C>T) pathogenic?

RNASEH2A p.Pro44= (c.132C>T) is classified Likely benign in RNASEH2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-07). Ultra-rare (popmax 0.085%, mid); Associated with Aicardi-Goutieres syndrome 4.

What condition is associated with RNASEH2A p.Pro44= (c.132C>T)?

RNASEH2A p.Pro44= (c.132C>T) is associated with Aicardi-Goutieres syndrome 4 (ClinVar).

How common is RNASEH2A p.Pro44= (c.132C>T) in the general population?

RNASEH2A p.Pro44= (c.132C>T) is ultra-rare (popmax 0.085%, mid) (gnomAD).

How is Aicardi-Goutières syndrome inherited?

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

RNASEH2A p.Pro44=

c.132C>T · rs752762157 · VCV1535335

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.085%, mid)

Conditions

Aicardi-Goutieres syndrome 4

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 -0.005	GERP -2.7, phastCons 0.75
Overall
CADD	8.604	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.085% Middle Eastern · 5/5,880 alleles

Filtering AF 0.0335% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0217%

Overall 0.00353% 57/1,613,776 alleles · ultra-rare exomes 54/1,461,562 · genomes 3/152,214 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.085%	1,176
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,290
Remaining individualsnot grpmax-eligible	0.00801%	12,490
Admixed American	0.005%	20,001
European (non-Finnish)	0.0028%	35,758
South Asian	0.0022%	45,535

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: RNASEH2A
Protein: p.Pro44=
Coding: c.132C>T
MANE Select: NM_006397
dbSNP: rs752762157
Type: single nucleotide variant
Location: chr19:12807012 (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 44: the rnase h type-2 domain

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 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.Arg235Gln Likely pathogenic ★★ same condition
RNASEH2A p.Trp219Ter Pathogenic/Likely pathogenic ★★ same condition
RNASEH2A c.411+3G>C Uncertain significance ★★ same condition
RNASEH2A p.Ala121Thr Uncertain significance ★★ ⚠ same condition
RNASEH2A p.Ala151Val 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-pro44 (accessed [today's date]).

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