Is CISD2 p.Arg57His (c.170G>A) pathogenic?

CISD2 p.Arg57His (c.170G>A) is classified Uncertain significance in CISD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-30). AlphaMissense: likely benign (0.2127); Very rare (popmax 0.00439%, sas); Associated with Wolfram syndrome 2.

What condition is associated with CISD2 p.Arg57His (c.170G>A)?

CISD2 p.Arg57His (c.170G>A) is associated with Wolfram syndrome 2 (ClinVar).

How common is CISD2 p.Arg57His (c.170G>A) in the general population?

CISD2 p.Arg57His (c.170G>A) is very rare (popmax 0.00439%, 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.Arg57His (c.170G>A)?

AlphaMissense predicts likely benign (score 0.2127) — an in-silico prediction, not a clinical call.

CISD2 p.Arg57His

c.170G>A · rs780388471 · VCV2420837

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2127 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Wolfram syndrome 2

Computational evidence

Protein change
AlphaMissense	0.2127	likely benign
REVEL	0.594	indeterminate
SaProt	LLR -10.62	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.1, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 16 kb · p 0.018 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,076 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00062% 10/1,613,874 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,769
Finnishnot grpmax-eligible	0.00156%	64,010
African / African-American	0.00134%	74,862
European (non-Finnish)	0.000339%	294,995

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.Arg57His
Coding: c.170G>A
MANE Select: NM_001008388
dbSNP: rs780388471
Type: single nucleotide variant
Location: chr4:102885282 (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 residue
CISD2 c.103+6C>A 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-p-arg57his (accessed [today's date]).

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