Is RNASEH2C p.Lys89= (c.267G>A) pathogenic?

RNASEH2C p.Lys89= (c.267G>A) is classified Likely benign in RNASEH2C (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-31). Very rare (popmax 0.00237%, nfe); Associated with Aicardi-Goutieres syndrome 3.

What condition is associated with RNASEH2C p.Lys89= (c.267G>A)?

RNASEH2C p.Lys89= (c.267G>A) is associated with Aicardi-Goutieres syndrome 3 (ClinVar).

How common is RNASEH2C p.Lys89= (c.267G>A) in the general population?

RNASEH2C p.Lys89= (c.267G>A) is very rare (popmax 0.00237%, nfe) (gnomAD).

How is Aicardi-Goutières syndrome inherited?

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

RNASEH2C p.Lys89=

c.267G>A · rs927863596 · VCV2745827

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Conditions

Aicardi-Goutieres syndrome 3

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 -0.56	GERP -2.2
Overall
CADD	9.144	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00237% European (non-Finnish) · 28/1,180,020 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.0018% 29/1,612,654 alleles · very rare exomes 28/1,461,862 · genomes 1/150,792 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00237%	42,144
Admixed American	0.00167%	59,990

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: RNASEH2C
Protein: p.Lys89=
Coding: c.267G>A
MANE Select: NM_032193
dbSNP: rs927863596
Type: single nucleotide variant
Location: chr11:65720323 (GRCh38)
Gene constraint: LOEUF 1.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.30 · 3 PDB

Full RNASEH2C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Aicardi-Goutieres syndrome 3 — 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

RNASEH2C p.Lys89fs Uncertain significance ★ same residue
RNASEH2C p.Arg69Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
RNASEH2C c.348+6C>T Uncertain significance ★★ same condition
RNASEH2C c.468+5G>A Uncertain significance ★★ same condition
RNASEH2C c.468+5G>C Uncertain significance ★★ same condition
RNASEH2C p.Arg145Leu Uncertain significance ★★ ⚠ same condition
RNASEH2C p.Asp117His Uncertain significance ★★ ⚠ same condition
RNASEH2C p.Asp164Gly 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/rnaseh2c-p-lys89 (accessed [today's date]).

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