Is CISD2 p.Pro80= (c.240G>A) pathogenic?

CISD2 p.Pro80= (c.240G>A) is classified Benign/Likely benign in CISD2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-21). Rare (popmax 0.198%, amr); Associated with Wolfram syndrome 2.

What condition is associated with CISD2 p.Pro80= (c.240G>A)?

CISD2 p.Pro80= (c.240G>A) is associated with Wolfram syndrome 2 (ClinVar).

How common is CISD2 p.Pro80= (c.240G>A) in the general population?

CISD2 p.Pro80= (c.240G>A) is rare (popmax 0.198%, amr) (gnomAD).

How is Wolfram syndrome inherited?

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

CISD2 p.Pro80=

c.240G>A · rs375529885 · VCV136775

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.198%, amr)

Conditions

Wolfram syndrome 2

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 0.34	GERP -3.9, phastCons 0.98
Overall
CADD	13.18	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.198% Admixed American · 119/60,014 alleles

Filtering AF 0.169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.158%

Overall 0.0336% 543/1,613,980 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.198%	504
South Asian	0.15%	665
Remaining individualsnot grpmax-eligible	0.056%	1,786
European (non-Finnish)	0.0208%	4,816
Finnishnot grpmax-eligible	0.00937%	10,671
African / African-American	0.00133%	75,050

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.Pro80=
Coding: c.240G>A
MANE Select: NM_001008388
dbSNP: rs375529885
Type: single nucleotide variant
Location: chr4:102885352 (GRCh38)
Gene constraint: LOEUF 0.437 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 90.19 · 4 PDB
Residue 80: a β-strand

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.Pro80Leu Uncertain significance ★★ same residue
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.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-pro80 (accessed [today's date]).

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