Is CISD2 c.103+6C>A pathogenic?

CISD2 c.103+6C>A is classified Uncertain significance in CISD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-02-05). Very rare (popmax 0.000511%, nfe); Associated with Wolfram syndrome 2.

What condition is associated with CISD2 c.103+6C>A?

CISD2 c.103+6C>A is associated with Wolfram syndrome 2 (ClinVar).

How common is CISD2 c.103+6C>A in the general population?

CISD2 c.103+6C>A is very rare (popmax 0.000511%, nfe) (gnomAD).

How is Wolfram syndrome inherited?

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

CISD2 c.103+6C>A

rs1271190440 · VCV1349559

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000511%, nfe)

Conditions

Wolfram syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +6	donor splice region (+6, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.6	GERP -1.9
Non-coding constraint	Z -1.03	1 kb window · o/e 1.07 · regional · uncalibrated
Overall
CADD	5.769	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000511% European (non-Finnish) · 6/1,173,202 alleles

Filtering AF 0.000184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000375% 6/1,599,368 alleles · very rare

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
Coding: c.103+6C>A
MANE Select: NM_001008388
dbSNP: rs1271190440
Type: single nucleotide variant
Location: chr4:102869193 (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 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
CISD2 c.104-9C>A Benign/Likely benign ★★ 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-c-103-plus-6c-a (accessed [today's date]).

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