Is CAND2 p.Ser449Arg (c.1347C>G) pathogenic?

CAND2 p.Ser449Arg (c.1347C>G) is classified Uncertain significance in CAND2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely pathogenic (0.9112); Rare (popmax 0.207%, nfe).

How common is CAND2 p.Ser449Arg (c.1347C>G) in the general population?

CAND2 p.Ser449Arg (c.1347C>G) is rare (popmax 0.207%, nfe) (gnomAD).

What do computational predictors say about CAND2 p.Ser449Arg (c.1347C>G)?

AlphaMissense predicts likely pathogenic (score 0.9112) — an in-silico prediction, not a clinical call.

CAND2 p.Ser449Arg

c.1347C>G · rs200578477 · VCV2348377

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9112 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.207%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9112	likely pathogenic
REVEL	0.28	benign-leaning
SaProt	LLR -12.92	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.2	GERP -4.4
Regional constraint	o/e 0.92	unconstrained · MANE · 27 kb · p 0.0026 · regional, not allelic
Overall
CADD	14.63	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 0.207% European (non-Finnish) · 2,441/1,179,964 alleles

Filtering AF 0.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.197%

Overall 0.166% 2,679/1,613,710 alleles · rare exomes 2,498/1,461,432 · genomes 181/152,278 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.207%	483
Middle Eastern	0.182%	551
Remaining individualsnot grpmax-eligible	0.133%	753
Admixed American	0.113%	882
Finnishnot grpmax-eligible	0.0707%	1,415
African / African-American	0.0213%	4,690
South Asian	0.0143%	7,006
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
East Asian	0.00223%	44,886

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.Ser449Arg
Coding: c.1347C>G
MANE Select: NM_001162499
dbSNP: rs200578477
Type: single nucleotide variant
Location: chr3:12815914 (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-ser449arg (accessed [today's date]).

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