Is CISD2 p.Ala31Val (c.92C>T) pathogenic?

CISD2 p.Ala31Val (c.92C>T) is classified Uncertain significance in CISD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-04). AlphaMissense: likely benign (0.0959); Very rare (popmax 0.00672%, eas).

How common is CISD2 p.Ala31Val (c.92C>T) in the general population?

CISD2 p.Ala31Val (c.92C>T) is very rare (popmax 0.00672%, eas) (gnomAD).

What do computational predictors say about CISD2 p.Ala31Val (c.92C>T)?

AlphaMissense predicts likely benign (score 0.0959) — an in-silico prediction, not a clinical call.

CISD2 p.Ala31Val

c.92C>T · rs765299352 · VCV1476052

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0959 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00672%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0959	likely benign
REVEL	0.154	moderately benign-leaning
SaProt	LLR -7.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.5	GERP -0.019, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 16 kb · p 0.018 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00672% East Asian · 3/44,664 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000894%

Overall 0.000343% 5/1,456,222 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00672%	14,888
Remaining individualsnot grpmax-eligible	0.0016%	62,344
South Asian	0.00112%	89,440

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.Ala31Val
Coding: c.92C>T
MANE Select: NM_001008388
dbSNP: rs765299352
Type: single nucleotide variant
Location: chr4:102869176 (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

Similar variants

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CISD2 p.Arg57His Uncertain significance ★★ ⚠ same type
CISD2 p.Asn87Ser Uncertain significance ★★ ⚠ same type
CISD2 p.Glu4Gln Uncertain significance ★★ ⚠ same type
CISD2 p.Pro61Leu Uncertain significance ★★ ⚠ same type
CISD2 p.Pro80Leu Uncertain significance ★★ ⚠ same type
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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-ala31val (accessed [today's date]).

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