Is CAND2 p.Arg489Cys (c.1465C>T) pathogenic?

CAND2 p.Arg489Cys (c.1465C>T) is classified Uncertain significance in CAND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely benign (0.1445); Rare (popmax 0.395%, nfe).

How common is CAND2 p.Arg489Cys (c.1465C>T) in the general population?

CAND2 p.Arg489Cys (c.1465C>T) is rare (popmax 0.395%, nfe) (gnomAD).

What do computational predictors say about CAND2 p.Arg489Cys (c.1465C>T)?

AlphaMissense predicts likely benign (score 0.1445) — an in-silico prediction, not a clinical call.

CAND2 p.Arg489Cys

c.1465C>T · VCV4218675

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1445 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.395%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1445	likely benign
REVEL	0.154	moderately benign-leaning
SaProt	LLR -11.24	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 27 kb · p 0.0026 · regional, not allelic
Overall
CADD	22.2	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 0.395% European (non-Finnish) · 4,662/1,179,402 alleles

Filtering AF 0.386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.382%

Overall 0.302% 4,864/1,612,418 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.395%	253
Remaining individualsnot grpmax-eligible	0.152%	657
African / African-American	0.0613%	1,631
Finnishnot grpmax-eligible	0.0346%	2,888
Ashkenazi Jewishnot grpmax-eligible	0.034%	2,944
Admixed American	0.0317%	3,150
South Asian	0.0077%	12,985
East Asian	0.00668%	14,961

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: CAND2
Protein: p.Arg489Cys
Coding: c.1465C>T
MANE Select: NM_001162499
Type: single nucleotide variant
Location: chr3:12816397 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.14 · 2 PDB

Full CAND2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAND2 p.Arg768Cys Uncertain significance ★★ ⚠ same type
CAND2 p.Arg1028Cys Benign ★★ same type
CAND2 p.Arg987Gln Benign ★★ ⚠ same type
CAND2 p.His709Arg Benign ★★ same type
CAND2 p.Ser491= Benign ★★ same type
CAND2 p.Ser999= Likely benign ★★ same type
CAND2 p.Ala1187Val Uncertain significance ★ ⚠ same type
CAND2 p.Ala1215Thr Uncertain significance ★ ⚠ same type

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/cand2-p-arg489cys (accessed [today's date]).

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