Is CISD2 p.Thr121Ile (c.362C>T) pathogenic?

CISD2 p.Thr121Ile (c.362C>T) is classified Uncertain significance in CISD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-18). AlphaMissense: likely pathogenic (0.9821); Very rare (popmax 0.0012%, sas); Associated with Wolfram syndrome 2.

What condition is associated with CISD2 p.Thr121Ile (c.362C>T)?

CISD2 p.Thr121Ile (c.362C>T) is associated with Wolfram syndrome 2 (ClinVar).

How common is CISD2 p.Thr121Ile (c.362C>T) in the general population?

CISD2 p.Thr121Ile (c.362C>T) is very rare (popmax 0.0012%, sas) (gnomAD).

How is Wolfram syndrome inherited?

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

What do computational predictors say about CISD2 p.Thr121Ile (c.362C>T)?

AlphaMissense predicts likely pathogenic (score 0.9821) — an in-silico prediction, not a clinical call.

CISD2 p.Thr121Ile

c.362C>T · VCV3589728

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9821 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0012%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Wolfram syndrome 2

Computational evidence

Protein change
AlphaMissense	0.9821	likely pathogenic
REVEL	0.386	indeterminate
SaProt	LLR -11.18	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.16	constrained · MANE · 2,036 bp · p 5.5e-09 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0012% South Asian · 1/83,064 alleles

Overall 0.000183% 2/1,093,238 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0012%	83,064
European (non-Finnish)	0.000118%	847,860

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.Thr121Ile
Coding: c.362C>T
MANE Select: NM_001008388
Type: single nucleotide variant
Location: chr4:102887384 (GRCh38)
Gene constraint: LOEUF 0.437 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 90.19 · 4 PDB
Residue 121: an α-helix

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-thr121ile (accessed [today's date]).

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