Is RNASEH2C p.Lys89fs (c.264_268del) pathogenic?

RNASEH2C p.Lys89fs (c.264268del) is classified Uncertain significance in RNASEH2C (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-23). Very rare (popmax 0.00267%, afr); Associated with Aicardi-Goutieres syndrome 3.

What condition is associated with RNASEH2C p.Lys89fs (c.264_268del)?

RNASEH2C p.Lys89fs (c.264_268del) is associated with Aicardi-Goutieres syndrome 3 (ClinVar).

How common is RNASEH2C p.Lys89fs (c.264_268del) in the general population?

RNASEH2C p.Lys89fs (c.264_268del) is very rare (popmax 0.00267%, afr) (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.Lys89fs

c.264_268del · rs1200334062 · VCV1981256

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Aicardi-Goutieres syndrome 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 4
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.2	GERP -0.23

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,914 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00025% 4/1,601,922 alleles · very rare exomes 4/1,451,048 · genomes 0/150,874 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,457
Remaining individualsnot grpmax-eligible	0.00161%	61,924
South Asian	0.00111%	90,438

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.Lys89fs
Coding: c.264_268del
MANE Select: NM_032193
dbSNP: rs1200334062
Type: Microsatellite
Location: chr11:65720322 (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.Lys89= Likely benign ★ same residue
RNASEH2C p.Lys90del Benign/Likely benign ★★ same condition
RNASEH2C p.Glu110del Uncertain significance ★ same condition
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

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-lys89fs (accessed [today's date]).

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