Is CISD2 p.Ter136Ser (c.407A>C) pathogenic?

CISD2 p.Ter136Ser (c.407A>C) is classified Uncertain significance in CISD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-26). Ultra-rare (popmax 0.0307%, amr); Associated with Wolfram syndrome 2.

What condition is associated with CISD2 p.Ter136Ser (c.407A>C)?

CISD2 p.Ter136Ser (c.407A>C) is associated with Wolfram syndrome 2 (ClinVar).

How common is CISD2 p.Ter136Ser (c.407A>C) in the general population?

CISD2 p.Ter136Ser (c.407A>C) is ultra-rare (popmax 0.0307%, amr) (gnomAD).

How is Wolfram syndrome inherited?

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

CISD2 p.Ter136Ser

c.407A>C · VCV3589729

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

stop-loss

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, amr)

Conditions

Wolfram syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	stop-loss	predicted loss-of-function in a LoF-intolerant gene
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.44 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.2	GERP -1.8, phastCons 0.9
Overall
CADD	10.92	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0307% Admixed American · 17/55,404 alleles

Filtering AF 0.0195% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00619% 50/807,194 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0307%	3,259
European (non-Finnish)	0.005%	19,988
Remaining individualsnot grpmax-eligible	0.00493%	20,267
African / African-American	0.00164%	60,876

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.Ter136Ser
Coding: c.407A>C
MANE Select: NM_001008388
Type: single nucleotide variant
Location: chr4:102887429 (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-ter136ser (accessed [today's date]).

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