Is CISD2 p.Arg20= (c.60G>C) pathogenic?

CISD2 p.Arg20= (c.60G>C) is classified Benign/Likely benign in CISD2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-13). Rare (popmax 0.589%, sas); Associated with Wolfram syndrome 2.

What condition is associated with CISD2 p.Arg20= (c.60G>C)?

CISD2 p.Arg20= (c.60G>C) is associated with Wolfram syndrome 2 (ClinVar).

How common is CISD2 p.Arg20= (c.60G>C) in the general population?

CISD2 p.Arg20= (c.60G>C) is rare (popmax 0.589%, sas) (gnomAD).

How is Wolfram syndrome inherited?

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

CISD2 p.Arg20=

c.60G>C · rs564095499 · VCV749103

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.589%, sas)

Conditions

Wolfram syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP -0.1, phastCons 1
Overall
CADD	12.48	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.589% South Asian · 533/90,540 alleles

Filtering AF 0.547% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.531%

Overall 0.0349% 563/1,612,716 alleles · rare exomes 539/1,460,358 · genomes 24/152,358 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.589%	170
Remaining individualsnot grpmax-eligible	0.0416%	2,402
East Asian	0.00223%	44,862
African / African-American	0.00133%	75,044
European (non-Finnish)	0.00017%	589,751

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: CISD2
Protein: p.Arg20=
Coding: c.60G>C
MANE Select: NM_001008388
dbSNP: rs564095499
Type: single nucleotide variant
Location: chr4:102869144 (GRCh38)
Gene constraint: LOEUF 0.437 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 90.19 · 4 PDB

Full CISD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Wolfram syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 1 000 000 (United Kingdom)

Similar variants

CISD2 c.103+6C>A Uncertain significance ★★ same condition
CISD2 p.Arg57Cys Uncertain significance ★★ ⚠ same condition
CISD2 p.Arg57His Uncertain significance ★★ ⚠ same condition
CISD2 p.Asn87Ser Uncertain significance ★★ ⚠ same condition
CISD2 p.Glu4Gln Uncertain significance ★★ ⚠ same condition
CISD2 p.Pro61Leu Uncertain significance ★★ ⚠ same condition
CISD2 p.Pro80Leu Uncertain significance ★★ same condition
CISD2 p.Thr28Ile 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/cisd2-p-arg20 (accessed [today's date]).

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