Is CCAR2 p.Ala214Ser (c.640G>T) pathogenic?

CCAR2 p.Ala214Ser (c.640G>T) is classified Uncertain significance in CCAR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-26). AlphaMissense: likely benign (0.0989); Very rare (popmax 0.00365%, nfe).

How common is CCAR2 p.Ala214Ser (c.640G>T) in the general population?

CCAR2 p.Ala214Ser (c.640G>T) is very rare (popmax 0.00365%, nfe) (gnomAD).

What do computational predictors say about CCAR2 p.Ala214Ser (c.640G>T)?

AlphaMissense predicts likely benign (score 0.0989) — an in-silico prediction, not a clinical call.

CCAR2 p.Ala214Ser

c.640G>T · rs138079032 · VCV3138196

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00365%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0989	likely benign
REVEL	0.219	benign-leaning
SaProt	LLR -6.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 12 kb · p 0.54 · regional, not allelic
Overall
CADD	22.8	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 0.00365% European (non-Finnish) · 43/1,179,602 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00267% 43/1,612,746 alleles · very rare

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: CCAR2
Protein: p.Ala214Ser
Coding: c.640G>T
MANE Select: NM_001393997
dbSNP: rs138079032
Type: single nucleotide variant
Location: chr8:22613072 (GRCh38)
Gene constraint: LOEUF 0.288 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.61 · 1 PDB
Residue 214: the 'disordered' region

Full CCAR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCAR2 p.Ala388= Benign ★★ same type
CCAR2 p.Ala794= Benign ★★ same type
CCAR2 p.Arg336= Likely benign ★★ same type
CCAR2 c.1990+1G>T Uncertain significance ★ same type
CCAR2 c.2521+1G>A Uncertain significance ★ same type
CCAR2 c.927+38G>C Uncertain significance ★ same type
CCAR2 p.Ala293Gly Uncertain significance ★ ⚠ same type
CCAR2 p.Ala388Val 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/ccar2-p-ala214ser (accessed [today's date]).

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