Is CAND2 p.His709Arg (c.2126A>G) pathogenic?

CAND2 p.His709Arg (c.2126A>G) is classified Benign in CAND2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-11). AlphaMissense: ambiguous (0.4013); Low-frequency (popmax 4.61%, amr).

How common is CAND2 p.His709Arg (c.2126A>G) in the general population?

CAND2 p.His709Arg (c.2126A>G) is low-frequency (popmax 4.61%, amr) (gnomAD).

What do computational predictors say about CAND2 p.His709Arg (c.2126A>G)?

AlphaMissense predicts ambiguous (score 0.4013) — an in-silico prediction, not a clinical call.

CAND2 p.His709Arg

c.2126A>G · rs180768267 · VCV778286

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4013 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.61%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4013	ambiguous
REVEL	0.266	benign-leaning
SaProt	LLR -5.49	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 27 kb · p 0.0026 · regional, not allelic
Overall
CADD	23.8	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 4.61% Admixed American · 2,768/60,006 alleles

Filtering AF 4.47% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.41%

Overall 0.254% 4,096/1,612,916 alleles · low-frequency

Ancestry group	Frequency	1 in
Admixed Americangrpmax	4.61%	22
East Asian	2.13%	47
Remaining individualsnot grpmax-eligible	0.342%	292
South Asian	0.0834%	1,198
African / African-American	0.0573%	1,745
European (non-Finnish)	0.00331%	30,255

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.His709Arg
Coding: c.2126A>G
MANE Select: NM_001162499
dbSNP: rs180768267
Type: single nucleotide variant
Location: chr3:12817058 (GRCh38)
Gene constraint: LOEUF 0.815 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.14 · 2 PDB
Residue 709: an α-helix

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.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
CAND2 p.Ala171Thr 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-his709arg (accessed [today's date]).

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